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Physiology 24: 45-57, 2009; doi:10.1152/physiol.00029.2008
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Physiology, Vol. 24, No. 1, 45-57, February 2009
© 2009 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

The Plastic Nature of the Vascular Wall: A Continuum of Remodeling Events Contributing to Control of Arteriolar Diameter and Structure

Luis A. Martinez-Lemus, Michael A. Hill and Gerald A. Meininger

Dalton Cardiovascular Research Center and Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri meiningerg{at}missouri.edu


   Abstract
 
The diameter of resistance arteries has a profound effect on the distribution of microvascular blood flow and the control of systemic blood pressure. Here, we review mechanisms that contribute to the regulation of resistance artery diameter, both acutely and chronically, their temporal characteristics, and their interdependence. Furthermore, we hypothesize the existence of a remodeling continuum that allows for the vascular wall to rapidly modify its structural characteristics, specifically through the re-positioning of vascular smooth muscle cells. Importantly, the concepts presented more closely link acute vasoregulatory responses with adaptive changes in vessel wall structure. These rapid structural adaptations provide resistance vessels the ability to maintain a desired diameter under presumed optimal energetic and mechanical conditions.


   Introduction
Top
 Introduction
Small Artery Remodeling:...
 Acute Control of Vascular...
 Transitioning from Acute to...
 Conclusions and Perspectives
 References
 
Traditionally the regulation of blood flow and local hemodynamics has been considered to occur either through short-term vasomotor responses or in the longer term via adaptive structural changes. Such adaptations of the vessel wall include structural remodeling, rarefaction, collateralization, and even angiogenesis. A newly emerging concept of plasticity of the vascular wall, however, is blurring the boundaries between these previously distinct processes and indeed may provide for a common underlying mechanistic link. The vessel wall instead of being considered a relatively static structure comprised of adventitia, contractile smooth muscle, and endothelium can now be seen as continually adapting with cells responding to the local mechanical, hemodynamic, and neurohumoral environments. Smooth muscle cells, for example, appear capable of changing their attachments, both between themselves and the surrounding extracellular matrix, thereby enabling active adjustment of their position within the vascular wall. This dynamic cellular repositioning conceivably allows wall stress to be borne by mechanisms other than active contraction. This review will examine current developments relating to the plasticity of the vascular wall in resistance vessels and propose the existence of a "remodeling continuum" that modulates the structural characteristics of components of the vessel wall over time. Such a system of remodeling is proposed to contribute to the active control of vascular diameter and tissue blood flow both acutely and chronically. In this article, particular emphasis is placed on the role played by the smooth muscle cells within the medial layer, since the contractile and structural characteristics of these cells are the primary means by which the diameter of small resistance vessels is actively controlled. Detailed discussions of remodeling involving changes in vessel number such as rarefaction and angiogenesis are not addressed, and the reader is referred to recent reviews on those subjects (11, 33, 81).


   Small Artery Remodeling: Expanding Our Current Definitions
Top
 Introduction
 Small Artery Remodeling:...
Acute Control of Vascular...
 Transitioning from Acute to...
 Conclusions and Perspectives
 References
 
Small arterial vessels (arteries and arterioles of internal diameter <300 µm) are vital to the regulation of hemodynamics. They provide more than 80% of the resistance to blood flow in the body and, as a consequence, are predominantly responsible for the control of blood pressure and the regional distribution of blood flow (42, 114).

The luminal diameter of resistance arteries is determined by the structural characteristics of the vessel and by the level of vasoconstriction exerted by the active contraction of the vascular smooth muscle cells contained within the vessel wall. Modifications in the structural characteristics of an already developed and functional blood vessel are controlled by vascular remodeling processes (30). At the cellular and molecular level, remodeling encompasses changes in subcellular cytoskeletal organization, cell-to-cell connections, and extracellular matrix composition. However, due to current limitations in our ability to define these micro- and nano-scale features of the vascular wall, specific macro-scale changes have been used to define remodeling. These macro-scale changes reflect gross tissue level modifications in luminal diameter, total wall thickness, and/or media and adventitia cross-sectional areas. For resistance vessels, the most widely used classification of macro-scale changes describing vascular remodeling was proposed by Mulvany et al. (119). In their scheme, the basis for establishing the occurrence of remodeling is a change in the passive (fully relaxed) luminal diameter of vessels measured at a standard intravascular pressure. Accordingly, inward remodeling occurs when the passive luminal diameter is decreased, and outward remodeling when passive luminal diameter is increased. This classification for remodeling was further refined by including changes in wall cross-sectional area. The type of remodeling is thus defined as hypertrophic, eutrophic, or hypotrophic if the cross-sectional area is increased, unchanged, or decreased, respectively. The strength of this classification system is that it allows for a clear identification of several remodeled vascular states using parameters commonly acquired during experimentation, namely vascular internal diameter and wall cross-sectional area. A necessary limitation, however, is that it identifies and defines specific endpoints or outcomes of what must be a continuum of parallel and/or serial events occurring at the molecular and cellular levels within all layers of the vascular wall.

Remodeling leading to macro-scale structural changes that alter the passive vascular diameter is known to occur in response to diverse physiological and pathological stimuli, including mechanical forces, neurohumoral factors, and paracrine agents. Table 1Go presents a broad survey of studies that have demonstrated remodeling of resistance arteries. It is noteworthy that most of the studies surveyed provide evidence for remodeling taking place after 2 days from the initiating stimulus, with only one study indicating remodeling may be observed within hours of stimulation. We propose that, during the remodeling process, significant changes begin to occur within and between the intracellular and extracellular components of the vascular wall before detectable changes in the passive diameter of the blood vessel take place. These changes can bring about alterations in vascular function. The events occurring early in the remodeling process are only beginning to be identified, and much work remains to improve our understanding of the initiating and transitional events that are linked to structural alteration of a vessel’s passive diameter. Here, our attention is focused on the mechanisms that allow the transition from acute to chronic vasoconstriction and inward remodeling. We provide experimental evidence that suggests the processes allowing for this transition begin during the acute phase of vasoconstriction and blur the boundaries between active contraction and inward remodeling. We will also provide evidence for a process of vascular smooth muscle rearrangement in the normal vascular wall that we hypothesize is adaptive remodeling in nature and related to regulation of vascular diameter. These remodeling changes may primarily be adaptive for the purposes of regulation of blood flow or blood pressure. However, these early events may also mark the initial phases of the maladaptive forms of remodeling that become associated with pathology.


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  		Table 1. Representative studies showing time-frame of structural remodeling in resistance arteries
 
Although the focus of this paper is on the role vascular smooth muscle plays in remodeling, it should be emphasized that many factors impact smooth muscle cell tone and hence could lead to remodeling involving the rearrangement of vascular smooth muscle within the vessel wall. There is also a vast literature that supports an important role for blood flow and the endothelium in vascular remodeling (3, 26, 95, 98, 105, 129, 168). Through flow-mediated (i.e., shear stress) release of vasoactive autacoids such as nitric oxide, endothelium-derived hyperpolarizing factor, prostaglandins, and growth factors, the endothelial cells are important participants in scenarios leading to remodeling of resistance vessel structure. Ultimately, the endothelium, with neural, hormonal, and metabolic stimuli, collectively influence vascular smooth muscle function and the structure of the vessel wall.


   Acute Control of Vascular Diameter
Top
 Introduction
 Small Artery Remodeling:...
 Acute Control of Vascular...
Transitioning from Acute to...
 Conclusions and Perspectives
 References
 
The contractile and malleable nature of the vascular smooth muscle cytoskeleton
Rapid changes in vascular diameter primarily depend on the contractile activation and interaction of actin with myosin in vascular smooth muscle cells. Changes in ion flux, membrane potential, and intracellular calcium concentration are accepted as principal events that control vascular smooth muscle cell contraction via calcium-calmodulin-dependent phosphorylation of the regulatory myosin light chains and subsequent actin-myosin cross-bridge cycling (78). Because resistance arteries from multiple vascular beds exhibit an intrinsic level of spontaneous tone (vasoconstriction), acute increments or decrements in vascular smooth muscle intracellular calcium induce rapid vasodilation or vasoconstriction, respectively. Accumulating evidence, however, indicates that additional calcium-independent processes are involved in the acute control of resistance artery diameter. These processes underscore the malleable nature of the vascular smooth muscle contractile machinery and include calcium sensitization (155) and actin filament remodeling (68), which, in contrast to calcium-dependent cross-bridge cycling, may contribute to more intermediate and chronic mechanisms controlling vascular diameter (FIGURE 1Go).


Figure 1
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  		FIGURE 1. VSMC acto-myosin cross-bridge cycling, calcium sensitization, and actin polymerization are involved in the acute active phase of vasoconstriction

Vascular smooth muscle cells (VSMC) located in the medial layer of resistance arteries actively contract to reduce the internal diameter of resistance arteries via processes involving the phosphorylation state of myosin-light chain (MLC20) and the remodeling of the actin cytoskeleton. Calcium-dependent pathways of MLC20 phosphorylation occur as intracellular calcium concentrations ([Ca2+]i) are elevated in response to extracellular calcium influx or the depletion of intracellular calcium stores in response to inositol triphosphate (IP3) and phospholipase C (PLC)-dependent signaling. Cytosolic calcium binds calmodulin (CaM) and activates myosin light chain kinase (MLCK), which in turn phosphorylates MLC20. Stimuli that activate G-protein-coupled receptors (GPCRs) and elevate [Ca2+]i are also capable of activating Rho guanine nucleotide exchange factors (RhoGEF), RhoA and Rho kinase (RhoK). This RhoK signaling cascade is a calcium-independent pathway that maintains pMLC20 via the phosphorylation and inactivation of myosin light chain phosphatase (MLCP). Actin polymerization participates in the acute phase of vasoconstriction as monomeric G-actin is incorporated into F-actin fibers and strengthens the cytoskeleton. This process requires the phosphorylation of paxillin and involves multiple focal adhesion-associated proteins with and without kinase activity such as integrins, talin, focal adhesion kinase (FAK), and possibly other non-receptor tyrosine kinases (NRTK) as well as tyrosine kinase receptors (TKR). IEL, internal elastic lamina. Figure is adapted from Refs. 69, 77.

 
The calcium sensitization process causes and/or maintains force generation via two major mechanisms that regulate the phosphorylation state of the 20-kDA myosin light chain (MLC20) independently of calcium-calmodulin-MLCK (MLC20 kinase) signaling. One of these mechanisms involves the capacity of multiple kinases, including integrin-linked kinase, p21-activated protein kinase, Rho kinase, and zipper-interacting protein kinase, to directly promote MLC20 phosphorylation in a MLCK-independent manner (77, 175). The other mechanism maintains phosphorylated MLC20 by reducing the activity of MLC20 phosphatase (MLCP). The inactivation of MLCP is mediated primarily by phosphorylation of its myosin phosphatase target subunit 1 (MYPT-1) (77, 155, 174, 175) but also via phosphorylation of the 17-kDA protein kinase C-potentiated inhibitory protein of type 1 protein phosphatase (CPI-17) (50, 77, 172). Importantly, both MLCP inactivation mechanisms can be activated by the Rho kinase signaling pathway. Moreover, multiple stimuli that induce calcium-dependent smooth muscle contraction also activate the small monomeric G-protein RhoA (64, 143, 144, 179), which is a primary step in the Rho kinase signaling pathway. Blockade of this pathway reduces the initial vasoconstrictor effect of both mechanical and neurohumoral stimuli, indicating that Rho kinase-dependent calcium sensitization plays a role in the acute phase of vasoconstriction (143, 144, 179).

Collectively, in maintaining force generation during the acute to intermediate phase of contraction (seconds to minutes), calcium-sensitization mechanisms are believed to reduce energy utilization by the vascular smooth muscle to more efficiently sustain vasoconstriction. This acute to intermediate phase transition in contraction occurs with notable changes in cell signaling. The initial spike in global intracellular calcium concentration caused by vasoconstrictor stimuli returns toward normal values within 5–30 min despite continuous presence of the stimulus (76, 135). The initial increase in phosphorylated MLC20 persists beyond the phase of elevated calcium due to preservation of calcium sensitization pathways (77, 135, 137) but eventually also declines, and yet contractile force is fully maintained. This strongly suggests that additional mechanisms likely involving cytoskeletal remodeling are activated that allow for the continuation of vaso-constriction in the absence of active actomyosin cross-bridge cycling and MLC20 phosphorylation.

The polymerization state of the actin cytoskeleton has been demonstrated to play a critical role in the acute phase of smooth muscle contraction in addition to the calcium-dependent and -independent modulation of MLC20 phosphorylation. Studies performed primarily in tracheal smooth muscle indicate that remodeling of the actin cytoskeleton is required for the full development of force induced by stimulation with contractile agonists (94, 113, 183). The process involves increased polymerization of actin, tyrosine phosphorylation of paxillin, the activation of the small GTP-binding proteins Rho and Cdc42, and conformational changes within focal adhesion sites involving specific focal adhesion proteins (161, 164, 180, 181). The end result is an increase in the F-to-G actin ratio, the reinforcement of actin stress fibers, and a generalized stiffening of the cytoskeleton. The importance of this dynamic remodeling of the cytoskeleton is highlighted by studies demonstrating that inhibition of actin polymerization attenuates the development of force induced by a number of agonists without a reduction in the extent of MLC20 phosphorylation. However, increased actin polymerization per se appears not to cause full force development in the absence of calcium-dependent MLC20 phosphorylation since inhibition of MLCK activity prevents the development of force induced by methacholine (89). This suggests that actin polymerization is necessary but not sufficient for the initial generation of force in airway smooth muscle. Collectively, these data add yet an additional paradigm to help describe the regulation of smooth muscle contraction that when extrapolated to vascular tissues would impact the regulation of vascular tone and diameter.

Indeed, as in airway smooth muscle, studies investigating the involvement of actin remodeling in vasoconstriction indicate that inhibition of actin polymerization blocks the development of full contractile force of both conduit and small resistance arteries (2, 36, 43, 44, 123, 124, 137, 142, 148, 176). However, in contrast to tracheal smooth muscle, inhibition of actin polymerization appears to interfere with vasoconstriction in a stimulus- and time-specific manner. For example, active myogenic contraction in resistance arterioles in response to increases in intravascular pressure is rapidly blocked (43, 61) by inhibition of actin polymerization without affecting the acute contraction induced by phenylephrine. Thus rapid actin filament remodeling appears to be an important component in pressure-dependent myogenic phenomena, i.e., the ability of blood vessels to contract in response to intraluminal pressure elevation. In comparison, the contractile response of larger carotid arteries to humoral stimulation gradually loses tension after inhibition of actin polymerization (136). Overall, the involvement of actin polymerization during the early phases of vasoconstriction highlights the dynamic plasticity of the vascular smooth muscle cytoskeleton and suggests that remodeling of intracellular structures plays a role in processes regulating vascular diameter.

Vascular smooth muscle cytoskeletal structures other than actin are also involved in the acute phase of vasoconstriction. Some studies have indicated that both intermediate filaments and microtubules participate in the initial development of force by smooth muscle. For intermediate filaments, it has been shown that phosphorylation, disassembly, and spatial reorientation of vimentin and desmin are needed for the development of force (162), whereas for microtubules it has been shown that tubular disruption induces vasoconstriction and augments vascular responsiveness to adrenergic stimulation via calcium sensitization processes dependent on the Rho kinase pathway (41, 130, 131). However, the overall roles of intermediate filaments or the microtubules on the regulation of contractile function in vascular smooth muscle cells leading to control of vascular diameter is poorly understood and requires further investigation.


   Transitioning from Acute to Longer-Term Control of Vascular Diameter
Top
 Introduction
 Small Artery Remodeling:...
 Acute Control of Vascular...
 Transitioning from Acute to...
Conclusions and Perspectives
 References
 
Compared with our knowledge of the mechanisms that rapidly adjust vascular diameter (seconds to minutes), less is known about the mechanisms that control vascular diameter more chronically (minutes to hours). When resistance arterioles are exposed to neurohumoral vasoconstrictors for extended periods (hours), it becomes clearly evident that their ability to return to pretreatment diameter is impaired following removal of the vasoconstrictor agonists (76, 108, 110). We propose that this apparent impairment in relaxation is a key observation indicating that a longer lasting change in some cellular and/or extracellular determinants of vascular wall structure has been initiated. Evidence indicates that activation of tyrosine phosphorylation pathways and the repositioning of smooth muscle cells within the vascular wall are involved in this process (76, 108). It is noteworthy that tyrosine kinase inhibition does not affect the initial phase of vasoconstriction but causes the vasoconstriction to wane in a time frame consistent with the reported reduction in MLC20 phosphorylation and prevents the inward remodeling associated with prolonged agonist stimulation (76, 108). These observations suggest that a continuum and coordinated set of mechanisms with unique temporal characteristics are responsible for the ability of arterioles to maintain a reduced diameter for extended periods of time and to initiate the inward remodeling process.

Central to these mechanisms is the extracellular matrix-integrin-cytoskeletal axis. This axis is predominantly responsible for maintaining the structural integrity of the vascular wall by providing anchoring mechanisms for cell-cell and cell-extracellular matrix interactions. In addition, it provides an avenue for the conduction of force and signals from the cell to the extracellular environment and vice versa. Importantly, evidence indicates that this axis, previously thought mostly as a structural scaffold for organ morphology, is indeed highly dynamic and an active participant in the control of vascular function (111). In the following sections, we consider a number of mechanisms that affect the characteristics of the major components of this axis as they participate in the prolonged control of vascular diameter.

The cytoskeleton: How independent are structural and contractile properties?
The cytoskeletal architecture provides the structural basis for cell morphology and actively participates in multiple cell signaling pathways, including those leading to cell migration, cell replication, and organ morphology (83, 85, 86). Cytoskeletal remodeling is initiated by signaling cascades that can be humoral and/or mechanical in nature. For vascular smooth muscle cells, vasoconstrictors and growth factors are common humoral factors that induce changes in tension development by the cytoskeleton through cross-bridge cycling and structural remodeling (43, 44, 136, 137, 163). As discussed above, increasing evidence indicates that the contractile process in smooth muscle is accompanied by changes in actin polymerization and the recruitment of structural proteins (including, vinculin, paxillin, talin and {alpha}-actinin) to the cytoplasmic side of focal adhesion sites (68, 161, 165, 180–183). It has been shown that these changes strengthen and stiffen the cytoskeleton, increasing the mechanical efficiency of the cell for the transmission of force, while reducing the elasticity of the cell over time. In vascular smooth muscle, this "cellular solidification" occurs concomitant to tyrosine phosphorylation of paxillin and F-actin fiber formation. Since tyrosine kinase inhibition prevents inward remodeling, we contend that this cellular solidification is in part responsible for the reduced vasodilatory capacity observed in resistance vessels that have been exposed for prolonged periods (hours) to vasoconstrictor agonists. The model that emerges from these data is that the vascular smooth muscle cell utilizes the cytoskeleton for dual purposes that are not easily separated into independent events. On the one hand, activation of smooth muscle cells leads to cross-bridge cycling and shortening while at the same time structural changes in assembly and disassembly of the cytoskeletal network lead to changes in the mechanical properties of the cell. Moreover, the activation of small GTP binding proteins responsible for the formation of cytoskeletal-dependent cellular extensions that occur during vaso-constriction suggest that strengthening of actin fibers may not be the only cytoskeletal remodeling that occurs during prolonged vasoconstriction. We propose that, inherent in this model, is the re-elongation of cells and the reversibility of strengthening cytoskeletal structures that permits the vascular smooth muscle cell to exit from a prolonged period of contraction to regain its initial length and mechanical state (FIGURE 2Go). Within the context of the vascular wall, cells would again optimize their functional range while the functional range of the vessel would shift to operate around a smaller diameter, as suggested by mathematical modeling (90). The precise mechanistic events that likely trigger this transition have yet to be identified.


Figure 2
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  		FIGURE 2. Sequence of events involved in vasoconstriction-induced inward eutrophic remodeling

Resistance arterioles under physiological intraluminal pressure normally develop spontaneous myogenic tone to between 70 and 50% of the passive arteriolar diameter. This spontaneous tone is primarily dependent on the concentration of intracellular calcium and actin polymerization and allows the vessel to further constrict or dilate in response to diverse stimuli. In response to agonist stimulation for vasoconstriction, arterioles further reduce their diameter though mechanisms that induce vascular smooth muscle cell (VSMC) acute contraction (see text for details). When the vasoconstrictor stimuli persist, VSMCs auto-regulate their length, changing their position within the arteriolar wall as vascular diameter remains reduced. This would enable VSMC to remain operational (constrict and relax) under a newly set arteriolar diameter. As the new arteriolar diameter is set, changes in the composition of the extracellular matrix (ECM) occur, likely including partial degradation and protein cross-linking. All these changes result in a blood vessel with a reduced diameter comprised of VSMC at or near their control lengths and putatively capable of inducing a near full range of arteriolar vasodilation and vasoconstriction, albeit at a reduced maximal passive diameter. MMPs, matrix metalloproteinases. Figure is adapted from Ref. 110.

 
Integrin receptors: dynamic sites of adhesion to the extracellular matrix
Integrins are the best characterized of the adhesion receptors for extracellular matrix components providing cells with the ability to adhere to surrounding connective tissue (FIGURE 3Go). Integrins consist of two subunits ({alpha} and β) noncovalently joined that connect the extracellular matrix with the cytoskeleton and other intracellular signaling proteins that accumulate at sites of focal adhesions (dense plaques). In the vascular wall, integrins act as receptors that participate in controlling vascular behavior (111). For example, {alpha}5β1 and {alpha}vβ3 integrins have been implicated in controlling basal vascular tone and the myogenic response of resistance vessels (109, 116, 117, 177, 178). It has also been observed that the expression of these two integrins is increased in mesenteric arteries from spontaneously hypertensive rats (88), possibly accounting for the increased vascular myogenic tone reported in these animals (58, 59, 149). In the mesenteric arterioles of the Ren2 rat model of hypertension, the {alpha}v integrin subunit is also upregulated (75). In these animals, hypertension is associated with arteriolar inward eutrophic remodeling, and inhibition of {alpha}vβ3 integrins prevents the remodeling process. Integrins {alpha}5β1 and {alpha}vβ3 are also known to be associated with vascular smooth muscle cell migration (10, 20) and remodeling of extracellular matrices (67, 84). Thus integrins appear important for processes leading to more chronic structural rearrangement of the vascular wall and extracellular matrix material. Collectively, these data provide credible reasons to believe that sites of integrin attachment are likely involved in the mechanisms that affect the rapid control of vascular diameter, the repositioning of vascular smooth muscle cells within the vascular wall, and the overall vascular remodeling process.


Figure 3
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  		FIGURE 3. Arteriolar remodeling mechanisms affect the ECM-integrin-cytoskeletal axis

Intracellularly, arteriolar remodeling mechanisms depend on the activation of multiple enzymes such as tissue-type transglutaminase (tTG), focal adhesion kinase (FAK), and other non-receptor tyrosine kinases (NRTK) that modify the structural characteristics of the cytoskeleton. At the cell membrane level, remodeling mechanisms such as those occurring in hypertension affect the activity and expression of integrins, the cellular receptors that connect the cytoskeleton with the ECM. Outside the cell, arteriolar remodeling mechanisms, such as those occurring in diabetes, remodel the ECM via enzymes that degrade (e.g., the MMPs) or crosslink ECM proteins (e.g., tTG), as well as via the production of new ECM.

 
Extracellular matrix plasticity
The extracellular matrix composition of the vascular wall is considered the major contributor to the visco-elastic characteristics of blood vessels (52, 170). In particular, the collagen-to-elastin ratio has been directly associated with the stiffness of the vascular wall. The elastic modulus of collagen is significantly greater than that of elastin (52, 170). Therefore, changes in the abundance or organization of these two major extracellular matrix components of the vascular wall would be expected to modify vascular compliance and as a consequence influence vasoregulation and the diameter that blood vessels attain at different intravascular pressures.

In health and disease, multiple physiological and pathological stimuli modify the collagen-to-elastin ratio and chronically influence vascular diameter. For example, aging is associated with an increased deposition of collagens type I and III in blood vessels. This augmented deposition of collagen reduces compliance and expands pulse pressure in the elderly (27, 152). In hypertension, sympathetic stimulation and activation of the renin-angiotensin system promotes the production of collagen by vascular smooth muscle cells and fibroblasts, thus contributing to extracellular matrix remodeling of the vascular wall (145, 166). In diabetes, there is also an increase in the vascular synthesis of extracellular matrix proteins including collagen and fibronectin (156). In addition, diabetes is associated with glycation and oxidation of proteins and lipids that lead to the formation of advanced glycation end products (AGEs) through molecular rearrangements that include the cross-linking of extra-cellular matrices (65). The cross-linking of collagens with AGEs makes collagens less sensitive to degradation, which in turn promotes matrix accumulation. Although these extracellular matrix changes are well documented to occur under the above conditions, the time course of the changes relative to their impact on vascular function is not well understood. Equally important for health reasons is understanding when and whether these changes become irreversible.

The time course and reversibility of protein cross-linking is of particular importance for the transition from hours to more chronic control of vascular diameter since recent evidence suggests that activation of the enzyme tissue type transglutaminase is involved in the remodeling of small resistance arteries (4, 7, 57, 128). Bakker et al. documented that activation of this enzyme is needed in the inward remodeling process occurring in response to prolonged vasoconstriction or reduced blood flow (4). In addition, the capacity of vascular smooth muscle cells in culture to contract collagen substrates also depends on the activity of this enzyme. Because collagen is a major determinant of the passive diameter of arterial vessels, Bakker et al. have proposed that inward remodeling occurs as tissue type transglutaminase acts to cross-link collagen resulting in "fixation" of the vessel wall around a reduced diameter (4, 7). The cross-linked collagen thus mechanically constrains the vascular wall. However, it has also been recognized that other activities of tissue-type transglutaminase may participate in vascular remodeling (7). These activities include the capacity of the enzyme to act as a G protein coupled to different agonist receptors, its capacity to participate in the formation of intracellular stress fibers, and its capacity to activate the Rho kinase signaling pathway. Collectively, activation of tissue-type trans-glutaminase may provide a natural pathway by which molecular cross-linking, including that of extracellular matrix proteins, participates in remodeling processes related to long-term regulation of blood flow and pressure.

Although collagen and elastin are the major contributors to the visco-elastic characteristics of the vascular wall, a number of additional extracellular matrix components affects both the compliance characteristics and vasoregulatory abilities of blood vessels. One example of these extracellular components is fibronectin. The content of fibronectin in blood vessels is particularly important not only because it modifies the mean stress and elastic modulus of the wall (24) but because recent evidence suggests that fibronectin is closely associated with the capacity of arteriolar smooth muscle cells to detect and react to mechanical forces via integrin receptors (159, 160) and with the capacity of contracting skeletal muscle to induce vasodilation of its adjacent vasculature (79). Thus changes in the amount of fibronectin in the vascular wall have the potential to significantly impact two functional characteristics of resistance vessels. One of these is the ability of blood vessels to respond with vasoconstriction to incremental changes in intraluminal pressure, a phenomenon known as the myogenic response (111). The other is the rapid vasodilatory response of arterioles to skeletal muscle activity (79). Importantly, total fibronectin has been reported to be increased in arteries from spontaneously hypertensive and diabetic rats (24, 156), and the mRNA for the splice variant, fibronectin IIIA+, is increased in inwardly remodeled arterioles from the Ren2 rat model of hypertension (75). This suggests that the changes in arteriolar intrinsic tone and passive diameter observed in hypertension and diabetes may be influenced by fibronectin content in the vascular wall.

The degradation of extracellular matrix components is also an integral part of the vascular remodeling process. In conduit arteries, the process of outward remodeling that increases the external diameter of vessels requires an increased activity of matrix metalloproteinases (MMPs) 2 and 9. MMPs are a family of enzymes produced by multiple cells in the vessel wall that degrade specific components of the extracellular matrix (25, 35, 62, 97). They are produced as proenzymes, and their net activity results from the balance that exists between proenzyme activation and their interaction with specific tissue inhibitors of MMPs (TIMPs). The increased activity of these enzymes in the outward remodeling process allows for the proliferation of vascular smooth muscle and adventitial cells, whereas in vascular remodeling processes occurring in response to vessel injury the controlled degradation and turnover of the extracellular matrix orchestrated by MMPs allows for vascular smooth muscle cell migration and neointima formation (19, 21, 22, 46, 49, 93, 107, 151). The extent to which MMPs are involved in more subtle changes in arteriolar remodeling that do not involve gross changes in vessel wall mass is not clear. Experimental evidence, however, strongly suggests that they participate in the acute and chronic control of resistance artery diameter (73, 106).

Recently, Hao et al. reported that adrenergic receptor stimulation of mesenteric arteries induces vaso-constriction in part through mechanisms that are dependent on MMP activation and further showed that MMP inhibition significantly reduced blood pressure in spontaneously hypertensive rats (73). Similarly, Luchessi et al. showed that pressure-mediated vasoconstriction of mesenteric resistance arteries involves activation of MMP-9 (106). Angiotensin II, a vasoconstrictor that induces inward eutrophic remodeling of resistance arteries (108), stimulates MMP secretion in isolated vascular smooth muscle cells (29). Given that these cells in the vascular wall are surrounded by multiple extracellular matrix proteins that provide anchoring points and structural support (32, 45, 127, 138, 152, 171), degradation and subsequent rearrangement of the matrix that surrounds them could have profound and rapid functional consequences on vasoregulation that with progression may lead to a more chronically altered vascular wall structure. Moreover, partial degradation of the extracellular matrix surrounding vascular smooth muscle cells is likely a necessary step for allowing the repositioning of cells during the remodeling process.

Overall, we have considered several possibilities that could account for longer-term maintenance of a reduced diameter and inward remodeling. These possible scenarios occurring alone or in concert are believed to be different from the mechanisms that produce initial constriction of the arteriole, albeit initiated by a common stimulus and all part of a continuum of interdependent events on a temporal scale. One possibility is that extensive intracellular remodeling occurs to return the cytoskeleton in vascular smooth muscle cells toward a pre-contraction control state. This possibility is supported by experimental data indicating that vascular smooth muscle cells tend to maintain a state of "tensional homeostasis" with relatively constant mechanical forces via remodeling of cytoskeletal and focal adhesion structures (120, 121). A second possibility is that smooth muscle cells within the vascular wall are capable of releasing their "contracted grip" on one another and/or on connective tissue elements, which allows cells to return toward their original length via the formation of cellular extensions and newly positioned cell-cell and cell-matrix focal adhesions. In support of this possibility, we previously reported that, during prolonged agonist-induced vaso-constriction, vascular smooth muscle cells re-elongate from their constricted length, changing their position within the arteriolar wall, as the vessel diameter remains reduced (110). In effect, individual smooth muscle cells change their degree of overlap by sliding over one another. This newly appreciated process likely involves remodeling of cytoskeletal structures and the formation of new focal adhesion sites as the cell changes position within the arteriolar wall (FIGURE 2Go). The involvement of proteins associated with the formation of cellular extensions and focal adhesions in the maintenance of prolonged vasoconstriction supports this concept (60, 82, 91, 136). A third possibility is that there are rapid changes in the extracellular matrix that shrink and stiffen the vascular structure. This possibility is supported by experimental data showing that the activity of the protein cross-linking enzyme, tissue type transglutaminase, is augmented during the remodeling process (4, 6, 7). Together, these changes would result in a blood vessel with a reduced diameter comprised of vascular smooth muscle cells at or near their control lengths and putatively capable of exhibiting a near full range of contractile activity. However, the range of this activity would now be shifted such that it occurs around a smaller diameter (FIGURE 2Go).

Because the structural characteristics of the vascular wall are significant determinants of the capacity of blood vessels to constrict and dilate, remodeling of resistance arteries is a phenomenon that contributes to hemodynamic dysfunction in a myriad of cardiovascular pathologies (FIGURE 3Go). Hypertension, intra-cerebral hemorrhages, overt and asymptomatic infarctions, stroke, and diabetes-dependent vasculopathies are all commonly associated with small artery disease. Moreover, inward eutrophic remodeling of resistance arteries characterized by an increased media-to-lumen ratio has been identified as the most prevalent vascular characteristic with the greatest predictive value for subsequent life-threatening cardiovascular events (48, 74, 87, 112, 118, 125, 139, 146). It remains to be determined when and how processes included in our proposed remodeling continuum initially adaptive in nature evolve into chronic maladaptive changes associated with vascular pathological conditions.


   Conclusions and Perspectives
Top
 Introduction
 Small Artery Remodeling:...
 Acute Control of Vascular...
 Transitioning from Acute to...
 Conclusions and Perspectives
References
 
A substantial amount of data exists on the characteristics of remodeled small arteries. In comparison, our knowledge on the progression of events that occurs from the outset of the process is considerably more limited. In the context of the vascular wall, specific areas in need of further attention include those involving the temporal changes in the micro-architecture and chemical properties of extracellular matrix, the dynamics of cell-matrix and cell-cell adhesions, and the integrated properties of the cytoskeleton. It is our contention that, related to these processes, a key regulatory mechanism involves positional plasticity of vascular smooth muscle cells within the vascular wall, which contributes to the short- and long-term control of vascular diameter.


   References
Top
 Introduction
 Small Artery Remodeling:...
 Acute Control of Vascular...
 Transitioning from Acute to...
 Conclusions and Perspectives
 References
 

  1. Aalkjaer C, Heagerty AM, Petersen KK, Swales JD, Mulvany MJ. Evidence for increased media thickness, increased neuronal amine uptake, and depressed excitation: contraction coupling in isolated resistance vessels from essential hypertensives. Circ Res 61: 181–186, 1987.[Abstract/Free Full Text]
  2. Adler KB, Krill J, Alberghini TV, Evans JN. Effect of cytochalasin D on smooth muscle contraction. Cell Motil 3: 545–551, 1983.[CrossRef][Web of Science][Medline]
  3. Amiri F, Virdis A, Neves MF, Iglarz M, Seidah NG, Touyz RM, Reudelhuber TL, Schiffrin EL. Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation 110: 2233–2240, 2004.[Abstract/Free Full Text]
  4. Bakker EN, Buus CL, Spaan JA, Perree J, Ganga A, Rolf TM, Sorop O, Bramsen LH, Mulvany MJ, Vanbavel E. Small artery remodeling depends on tissue-type transglutaminase. Circ Res 96: 119–126, 2005.[Abstract/Free Full Text]
  5. Bakker EN, Buus CL, VanBavel E, Mulvany MJ. Activation of resistance arteries with endothelin-1: from vasoconstriction to functional adaptation and remodeling. J Vasc Res 41: 174–182, 2004.[CrossRef][Web of Science][Medline]
  6. Bakker EN, Pistea A, Spaan JA, Rolf T, de Vries CJ, van Rooijen N, Candi E, VanBavel E. Flow-dependent remodeling of small arteries in mice deficient for tissue-type transglutaminase: possible compensation by macrophage-derived factor XIII. Circ Res 99: 86–92, 2006.[Abstract/Free Full Text]
  7. Bakker EN, Pistea A, VanBavel E. Transglutaminases in vascular biology: relevance for vascular remodeling and atherosclerosis. J Vasc Res 45: 271–278, 2008.[CrossRef][Web of Science][Medline]
  8. Bakker EN, van Der Meulen ET, Spaan JA, VanBavel E. Organoid culture of cannulated rat resistance arteries: effect of serum factors on vasoactivity and remodeling. Am J Physiol Heart Circ Physiol 278: H1233–H1240, 2000.[Abstract/Free Full Text]
  9. Bakker EN, van der Meulen ET, van den Berg BM, Everts V, Spaan JA, VanBavel E. Inward remodeling follows chronic vasoconstriction in isolated resistance arteries. J Vasc Res 39: 12–20, 2002.[CrossRef][Web of Science][Medline]
  10. Barillari G, Albonici L, Incerpi S, Bogetto L, Pistritto G, Volpi A, Ensoli B, Manzari V. Inflammatory cytokines stimulate vascular smooth muscle cells locomotion and growth by enhancing alpha5beta1 integrin expression and function. Atherosclerosis 154: 377–385, 2001.[CrossRef][Web of Science][Medline]
  11. Battegay EJ, de Miguel LS, Petrimpol M, Humar R. Effects of anti-hypertensive drugs on vessel rarefaction. Curr Opin Pharmacol 7: 151–157, 2007.[CrossRef][Web of Science][Medline]
  12. Baumbach GL, Hajdu MA. Mechanics and composition of cerebral arterioles in renal and spontaneously hypertensive rats. Hypertension 21: 816–826, 1993.[Abstract/Free Full Text]
  13. Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension 13: 968–972, 1989.[Abstract/Free Full Text]
  14. Baumbach GL, Heistad DD, Siems JE. Effect of sympathetic nerves on composition and distensibility of cerebral arterioles in rats. J Physiol 416: 123–140, 1989.[Abstract/Free Full Text]
  15. Baumbach GL, Siems JE, Heistad DD. Effects of local reduction in pressure on distensibility and composition of cerebral arterioles. Circ Res 68: 338–351, 1991.[Abstract/Free Full Text]
  16. Baumbach GL, Sigmund CD, Faraci FM. Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen. Hypertension 41: 50–55, 2003.[Abstract/Free Full Text]
  17. Baumbach GL, Sigmund CD, Faraci FM. Structure of cerebral arterioles in mice deficient in expression of the gene for endothelial nitric oxide synthase. Circ Res 95: 822–829, 2004.[Abstract/Free Full Text]
  18. Baumbach GL, Walmsley JG, Hart MN. Composition and mechanics of cerebral arterioles in hypertensive rats. Am J Pathol 133: 464–471, 1988.[Abstract]
  19. Bendeck MP, Conte M, Zhang M, Nili N, Strauss BH, Farwell SM. Doxycycline modulates smooth muscle cell growth, migration, and matrix remodeling after arterial injury. Am J Pathol 160: 1089–1095, 2002.[Abstract/Free Full Text]
  20. Bendeck MP, Irvin C, Reidy M, Smith L, Mulholland D, Horton M, Giachelli CM. Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin. Arterioscler Thromb Vasc Biol 20: 1467–1472, 2000.[Abstract/Free Full Text]
  21. Bendeck MP, Irvin C, Reidy MA. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ Res 78: 38–43, 1996.[Abstract/Free Full Text]
  22. Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res 75: 539–545, 1994.[Abstract/Free Full Text]
  23. Beyer AM, Baumbach GL, Halabi CM, Modrick ML, Lynch CM, Gerhold TD, Ghoneim SM, de Lange WJ, Keen HL, Tsai YS, Maeda N, Sigmund CD, Faraci FM. Interference with PPARgamma signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling. Hypertension 51: 867–871, 2008.[Abstract/Free Full Text]
  24. Bezie Y, Lamaziere JM, Laurent S, Challande P, Cunha RS, Bonnet J, Lacolley P. Fibronectin expression and aortic wall elastic modulus in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 18: 1027–1034, 1998.[Abstract/Free Full Text]
  25. Bobik A, Tkachuk V. Metalloproteinases and plasminogen activators in vessel remodeling. Curr Hypertens Rep 5: 466–472, 2003.[Web of Science][Medline]
  26. Bouvet C, Belin de Chantemele E, Guihot AL, Vessieres E, Bocquet A, Dumont O, Jardel A, Loufrani L, Moreau P, Henrion D. Flow-induced remodeling in resistance arteries from obese Zucker rats is associated with endothelial dysfunction. Hypertension 50: 248–254, 2007.[Abstract/Free Full Text]
  27. Briones AM, Salaices M, Vila E. Mechanisms underlying hypertrophic remodeling and increased stiffness of mesenteric resistance arteries from aged rats. J Gerontol A Biol Sci Med Sci 62: 696–706, 2007.[Web of Science][Medline]
  28. Briones AM, Xavier FE, Arribas SM, Gonzalez MC, Rossoni LV, Alonso MJ, Salaices M. Alterations in structure and mechanics of resistance arteries from ouabain-induced hypertensive rats. Am J Physiol Heart Circ Physiol 291: H193–H201, 2006.[Abstract/Free Full Text]
  29. Browatzki M, Larsen D, Pfeiffer CA, Gehrke SG, Schmidt J, Kranzhofer A, Katus HA, Kranzhofer R. Angiotensin II stimulates matrix metalloproteinase secretion in human vascular smooth muscle cells via nuclear factor-kappaB and activator protein 1 in a redox-sensitive manner. J Vasc Res 42: 415–423, 2005.[CrossRef][Web of Science][Medline]
  30. Bund SJ, Lee RM. Arterial structural changes in hypertension: a consideration of methodology, terminology and functional consequence. J Vasc Res 40: 547–557, 2003.[Web of Science][Medline]
  31. Buus CL, Pourageaud F, Fazzi GE, Janssen G, Mulvany MJ, De Mey JG. Smooth muscle cell changes during flow-related remodeling of rat mesenteric resistance arteries. Circ Res 89: 180–186, 2001.[Abstract/Free Full Text]
  32. Byzova TV, Rabbani R, D’Souza SE, Plow EF. Role of integrin alpha(v)beta3 in vascular biology. Thromb Haemost 80: 726–734, 1998.[Web of Science][Medline]
  33. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 438: 932–936, 2005.[CrossRef][Medline]
  34. Ceiler DL, De Mey JG. Chronic NG-nitro-L-arginine methyl ester treatment does not prevent flow-induced remodeling in mesenteric feed arteries and arcading arterioles. Arterioscler Thromb Vasc Biol 20: 2057–2063, 2000.[Abstract/Free Full Text]
  35. Chase AJ, Newby AC. Regulation of matrix metalloproteinase (matrixin) genes in blood vessels: a multi-step recruitment model for pathological remodelling. J Vasc Res 40: 329–343, 2003.[CrossRef][Web of Science][Medline]
  36. Chen X, Pavlish K, Zhang HY, Benoit JN. Effects of chronic portal hypertension on agonist-induced actin polymerization in small mesenteric arteries. Am J Physiol Heart Circ Physiol 290: H1915–H1921, 2006.[Abstract/Free Full Text]
  37. Chillon JM, Baumbach GL. Effects of an angiotensin-converting enzyme inhibitor and a beta-blocker on cerebral arterioles in rats. Hypertension 33: 856–861, 1999.[Abstract/Free Full Text]
  38. Chillon JM, Baumbach GL. Effects of chronic nitric oxide synthase inhibition on cerebral arterioles in Wistar-Kyoto rats. J Hypertens 22: 529–534, 2004.[CrossRef][Web of Science][Medline]
  39. Chillon JM, Baumbach GL. Effects of indapamide, a thiazide-like diuretic, on structure of cerebral arterioles in hypertensive rats. Hypertension 43: 1092–1097, 2004.[Abstract/Free Full Text]
  40. Chillon JM, Heistad DD, Baumbach GL. Effects of endothelin receptor inhibition on cerebral arterioles in hypertensive rats. Hypertension 27: 794–798, 1996.[Abstract/Free Full Text]
  41. Chitaley K, Webb RC. Microtubule depolymerization facilitates contraction of rat aorta via activation of Rho-kinase. Vasc Pharmacol 38: 157–161, 2002.[CrossRef]
  42. Christensen KL, Mulvany MJ. Location of resistance arteries. J Vasc Res 38: 1–12, 2001.[Web of Science][Medline]
  43. Cipolla MJ, Gokina NI, Osol G. Pressure-induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior. FASEB J 16: 72–76, 2002.[Abstract/Free Full Text]
  44. Cipolla MJ, Osol G. Vascular smooth muscle actin cytoskeleton in cerebral artery forced dilatation. Stroke 29: 1223–1228, 1998.[Abstract/Free Full Text]
  45. Clyman RI, Mauray F, Kramer RH. Beta 1 and beta 3 integrins have different roles in the adhesion and migration of vascular smooth muscle cells on extracellular matrix. Exp Cell Res 200: 272–284, 1992.[CrossRef][Web of Science][Medline]
  46. Courtman DW, Franco CD, Meng Q, Bendeck MP. Inward remodeling of the rabbit aorta is blocked by the matrix metalloproteinase inhibitor doxycycline. J Vasc Res 41: 157–165, 2004.[CrossRef][Web of Science][Medline]
  47. Dao HH, Martens FM, Lariviere R, Yamaguchi N, Cernacek P, de Champlain J, Moreau P. Transient involvement of endothelin in hypertrophic remodeling of small arteries. J Hypertens 19: 1801–1812, 2001.[CrossRef][Web of Science][Medline]
  48. De Ciuceis C, Porteri E, Rizzoni D, Rizzardi N, Paiardi S, Boari GE, Miclini M, Zani F, Muiesan ML, Donato F, Salvetti M, Castellano M, Tiberio GA, Giulini SM, Agabiti Rosei E. Structural alterations of subcutaneous small-resistance arteries may predict major cardiovascular events in patients with hypertension. Am J Hypertens 20: 846–852, 2007.[CrossRef][Web of Science][Medline]
  49. de Smet BJ, de Kleijn D, Hanemaaijer R, Verheijen JH, Robertus L, van Der Helm YJ, Borst C, Post MJ. Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan micropig. Circulation 101: 2962–2967, 2000.[Abstract/Free Full Text]
  50. Deng JT, Sutherland C, Brautigan DL, Eto M, Walsh MP. Phosphorylation of the myosin phosphatase inhibitors, CPI-17 and PHI-1, by integrin-linked kinase. Biochem J 367: 517–524, 2002.[CrossRef][Web of Science][Medline]
  51. Deng LY, Schiffrin EL. Effects of endothelin-1 and vasopressin on resistance arteries of spontaneously hypertensive rats. Am J Hypertens 5: 817–822, 1992.[Web of Science][Medline]
  52. Dobrin PB. Mechanical properties of arteries. Physiol Rev 58: 397–460, 1978.[Free Full Text]
  53. Dorrance AM, Rupp NC, Nogueira EF. Mineralocorticoid receptor activation causes cerebral vessel remodeling and exacerbates the damage caused by cerebral ischemia. Hypertension 47: 590–595, 2006.[Abstract/Free Full Text]
  54. Dumont O, Loufrani L, Henrion D. Key role of the NO-pathway and matrix metalloprotease-9 in high blood flow-induced remodeling of rat resistance arteries. Arterioscler Thromb Vasc Biol 27: 317–324, 2007.[Abstract/Free Full Text]
  55. Dupuis F, Atkinson J, Liminana P, Chillon JM. Captopril improves cerebrovascular structure and function in old hypertensive rats. Br J Pharmacol 144: 349–356, 2005.[CrossRef][Web of Science][Medline]
  56. Dupuis F, Atkinson J, Liminana P, Chillon JM. Comparative effects of the angiotensin II receptor blocker, telmisartan, and the angiotensin-converting enzyme inhibitor, ramipril, on cerebrovascular structure in spontaneously hypertensive rats. J Hypertens 23: 1061–1066, 2005.[Web of Science][Medline]
  57. Eftekhari A, Rahman A, Schaebel LH, Chen H, Rasmussen CV, Aalkjaer C, Buus CL, Mulvany MJ. Chronic cystamine treatment inhibits small artery remodelling in rats. J Vasc Res 44: 471–482, 2007.[CrossRef][Web of Science][Medline]
  58. Falcone JC, Granger HJ, Meininger GA. Enhanced myogenic activation in skeletal muscle arterioles from spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 265: H1847–H1855, 1993.[Abstract/Free Full Text]
  59. Falcone JC, Meininger GA. Endothelin mediates a component of the enhanced myogenic responsiveness of arterioles from hypertensive rats. Microcirculation 6: 305–313, 1999.[CrossRef][Web of Science][Medline]
  60. Fernstrom K, Farmer P, Ali MS. Cytoskeletal remodeling in vascular smooth muscle cells in response to angiotensin II-induced activation of the SHP-2 tyrosine phosphatase. J Cell Physiol 205: 402–413, 2005.[CrossRef][Web of Science][Medline]
  61. Flavahan NA, Bailey SR, Flavahan WA, Mitra S, Flavahan S. Imaging remodeling of the actin cytoskeleton in vascular smooth muscle cells after mechanosensitive arteriolar constriction. Am J Physiol Heart Circ Physiol 288: H660–H669, 2005.[Abstract/Free Full Text]
  62. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90: 251–262, 2002.[Abstract/Free Full Text]
  63. Girardot D, Demeilliers B, deBlois D, Moreau P. ERK1/2-mediated vasoconstriction normalizes wall stress in small mesenteric arteries during NOS inhibition in vivo. J Cardiovasc Pharmacol 42: 339–347, 2003.[CrossRef][Web of Science][Medline]
  64. Gokina NI, Park KM, McElroy-Yaggy K, Osol G. Effects of Rho kinase inhibition on cerebral artery myogenic tone and reactivity. J Appl Physiol 98: 1940–1948, 2005.[Abstract/Free Full Text]
  65. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114: 597–605, 2006.[Abstract/Free Full Text]
  66. Gonzalez JM, Briones AM, Somoza B, Daly CJ, Vila E, Starcher B, McGrath JC, Gonzalez MC, Arribas SM. Postnatal alterations in elastic fiber organization precede resistance artery narrowing in SHR. Am J Physiol Heart Circ Physiol 291: H804–H812, 2006.[Abstract/Free Full Text]
  67. Grundstrom G, Mosher DF, Sakai T, Rubin K. Integrin alphavbeta3 mediates platelet-derived growth factor-BB-stimulated collagen gel contraction in cells expressing signaling deficient integrin alpha2beta1. Exp Cell Res 291: 463–473, 2003.[CrossRef][Web of Science][Medline]
  68. Gunst SJ, Fredberg JJ. The first three minutes: smooth muscle contraction, cytoskeletal events, and soft glasses. J Appl Physiol 95: 413–425, 2003.[Abstract/Free Full Text]
  69. Gunst SJ, Zhang W. Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction. Am J Physiol Cell Physiol 295: C576–C587, 2008.[Abstract/Free Full Text]
  70. Hajdu MA, Baumbach GL. Mechanics of large and small cerebral arteries in chronic hypertension. Am J Physiol Heart Circ Physiol 266: H1027–H1033, 1994.[Abstract/Free Full Text]
  71. Hajdu MA, Heistad DD, Baumbach GL. Effects of antihypertensive therapy on mechanics of cerebral arterioles in rats. Hypertension 17: 308–316, 1991.[Abstract/Free Full Text]
  72. Hajdu MA, Heistad DD, Siems JE, Baumbach GL. Effects of aging on mechanics and composition of cerebral arterioles in rats. Circ Res 66: 1747–1754, 1990.[Abstract/Free Full Text]
  73. Hao L, Du M, Lopez-Campistrous A, Fernandez-Patron C. Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway. Circ Res 94: 68–76, 2004.[Abstract/Free Full Text]
  74. Heagerty AM, Aalkjaer C, Bund SJ, Korsgaard N, Mulvany MJ. Small artery structure in hypertension. Dual processes of remodeling and growth. Hypertension 21: 391–397, 1993.[Free Full Text]
  75. Heerkens EH, Shaw L, Ryding A, Brooker G, Mullins JJ, Austin C, Ohanian V, Heagerty AM. AlphaV integrins are necessary for eutrophic inward remodeling of small arteries in hypertension. Hypertension 47: 281–287, 2006.[Abstract/Free Full Text]
  76. Hill MA, Potocnik SJ, Martinez-Lemus LA, Meininger GA. Delayed arteriolar relaxation after prolonged agonist exposure: functional remodeling involving tyrosine phosphorylation. Am J Physiol Heart Circ Physiol 285: H849–H856, 2003.[Abstract/Free Full Text]
  77. Hirano K. Current topics in the regulatory mechanism underlying the Ca2+ sensitization of the contractile apparatus in vascular smooth muscle. J Pharm Sci 104: 109–115, 2007.[CrossRef][Web of Science]
  78. Hirano K, Hirano M, Kanaide H. Regulation of myosin phosphorylation and myofilament Ca2+ sensitivity in vascular smooth muscle. J Smooth Muscle Res 40: 219–236, 2004.[CrossRef][Medline]
  79. Hocking DC, Titus PA, Sumagin R, Sarelius IH. Extracellular matrix fibronectin mechanically couples skeletal muscle contraction with local vasodilation. Circ Res 102: 372–379, 2008.[Abstract/Free Full Text]
  80. Hong H, Aksenov S, Guan X, Fallon JT, Waters D, Chen C. Remodeling of small intramyocardial coronary arteries distal to a severe epicardial coronary artery stenosis. Arterioscler Thromb Vasc Biol 22: 2059–2065, 2002.[Abstract/Free Full Text]
  81. Horowitz A, Simons M. Branching morphogenesis. Circ Res 103: 784–795, 2008.[Abstract/Free Full Text]
  82. Hu H, Bliss JM, Wang Y, Colicelli J. RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration. Curr Biol 15: 815–823, 2005.[CrossRef][Web of Science][Medline]
  83. Humphrey JD. Vascular adaptation and mechanical homeostasis at tissue, cellular, and sub-cellular levels. Cell Biochem Biophys 50: 53–78, 2008.[CrossRef][Web of Science][Medline]
  84. Huveneers S, Truong H, Fassler R, Sonnenberg A, Danen EH. Binding of soluble fibronectin to integrin alpha5beta1: link to focal adhesion redistribution and contractile shape. J Cell Sci 121: 2452–2462, 2008.[Abstract/Free Full Text]
  85. Ingber DE, Tensegrity I. Cell structure and hierarchical systems biology. J Cell Sci 116: 1157–1173, 2003.[Abstract/Free Full Text]
  86. Ingber Tensegrity DE 2nd. How structural networks influence cellular information processing networks. J Cell Sci 116: 1397–1408, 2003.[Abstract/Free Full Text]
  87. Intengan HD, Schiffrin EL. Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants. Hypertension 36: 312–318, 2000.[Abstract/Free Full Text]
  88. Intengan HD, Thibault G, Li JS, Schiffrin EL. Resistance artery mechanics, structure, and extracellular components in spontaneously hypertensive rats : effects of angiotensin receptor antagonism and converting enzyme inhibition. Circulation 100: 2267–2275, 1999.[Abstract/Free Full Text]
  89. Ito S, Kume H, Honjo H, Kodama I, Katoh H, Hayashi H, Shimokata K. ML-9, a myosin light chain kinase inhibitor, reduces intracellular Ca2+ concentration in guinea pig trachealis. Eur J Pharmacol 486: 325–333, 2004.[CrossRef][Web of Science][Medline]
  90. Jacobsen JC, Mulvany MJ, Holstein-Rathlou NH. A mechanism for arteriolar remodeling based on maintenance of smooth muscle cell activation. Am J Physiol Regul Integr Comp Physiol 294: R1379–R1389, 2008.[Abstract/Free Full Text]
  91. Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Develop Biol 21: 247–269, 2005.[CrossRef][Web of Science][Medline]
  92. Jimenez-Altayo F, Martin A, Rojas S, Justicia C, Briones AM, Giraldo J, Planas AM, Vila E. Transient middle cerebral artery occlusion causes different structural, mechanical, and myogenic alterations in normotensive and hypertensive rats. Am J Physiol Heart Circ Physiol 293: H628–H635, 2007.[Abstract/Free Full Text]
  93. Johnson C, Galis ZS. Matrix metalloproteinase-2 and -9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization. Arterioscler Thromb Vasc Biol 24: 54–60, 2004.[Abstract/Free Full Text]
  94. Jones KA, Perkins WJ, Lorenz RR, Prakash YS, Sieck GC, Warner DO. F-actin stabilization increases tension cost during contraction of permeabilized airway smooth muscle in dogs. J Physiol 519: 527–538, 1999.[Abstract/Free Full Text]
  95. Koller A. Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension. Microcirculation 9: 277–294, 2002.[CrossRef][Web of Science][Medline]
  96. Korsgaard N, Aalkjaer C, Heagerty AM, Izzard AS, Mulvany MJ. Histology of subcutaneous small arteries from patients with essential hypertension. Hypertension 22: 523–526, 1993.[Abstract/Free Full Text]
  97. Kuzuya M, Iguchi A. Role of matrix metalloproteinases in vascular remodeling. J Atheroscler Thromb 10: 275–282, 2003.[Medline]
  98. Langille BL. Remodeling of developing and mature arteries: endothelium, smooth muscle, and matrix. J Cardiovasc Pharmacol 21, Suppl 1: S11–S17, 1993.
  99. Laurant P, Adrian M, Berthelot A. Effect of age on mechanical properties of rat mesenteric small arteries. Can J Physiol Pharmacol 82: 269–275, 2004.[CrossRef][Web of Science][Medline]
  100. Ledingham JM, Phelan EL, Cross MA, Laverty R. Prevention of increases in blood pressure and left ventricular mass and remodeling of resistance arteries in young New Zealand genetically hypertensive rats: the effects of chronic treatment with valsartan, enalapril and felodipine. J Vasc Res 37: 134–145, 2000.[CrossRef][Web of Science][Medline]
  101. Li JS, Lariviere R, Schiffrin EL. Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats. Evidence for a role of endothelin in vascular hypertrophy. Hypertension 24: 183–188, 1994.[Abstract/Free Full Text]
  102. Li JS, Schiffrin EL. Effect of calcium channel blockade or angiotensin-converting enzyme inhibition on structure of coronary, renal, and other small arteries in spontaneously hypertensive rats. J Cardiovasc Pharmacol 28: 68–74, 1996.[CrossRef][Web of Science][Medline]
  103. Li JS, Schiffrin EL. Effect of short-term treatment of SHR with the novel calcium channel antagonist mibefradil on function of small arteries. Am J Hypertens 10: 94–100, 1997.[CrossRef][Web of Science][Medline]
  104. Li JS, Sharifi AM, Schiffrin EL. Effect of AT1 angiotensin-receptor blockade on structure and function of small arteries in SHR. J Cardiovasc Pharmacol 30: 75–83, 1997.[CrossRef][Web of Science][Medline]
  105. Loufrani L, Henrion D. Role of the cytoskeleton in flow (shear stress)-induced dilation and remodeling in resistance arteries. Med Biol Eng Comput 46: 451–460, 2008.[CrossRef][Web of Science][Medline]
  106. Lucchesi PA, Sabri A, Belmadani S, Matrougui K. Involvement of metalloproteinases 2/9 in epidermal growth factor receptor transactivation in pressure-induced myogenic tone in mouse mesenteric resistance arteries. Circulation 110: 3587–3593, 2004.[Abstract/Free Full Text]
  107. Margolin L, Fishbein I, Banai S, Golomb G, Reich R, Perez LS, Gertz SD. Metalloproteinase inhibitor attenuates neointima formation and constrictive remodeling after angioplasty in rats: augmentative effect of alpha(v)beta(3) receptor blockade. Atherosclerosis 163: 269–277, 2002.[CrossRef][Web of Science][Medline]
  108. Martinez-Lemus LA. Persistent agonist-induced vasoconstriction is not required for angiotensin II to mediate inward remodeling of isolated arterioles with myogenic tone. J Vasc Res 45: 211–221, 2008.[CrossRef][Web of Science][Medline]
  109. Martinez-Lemus LA, Crow T, Davis MJ, Meininger GA. Alphavbeta3- and alpha5beta1-integrin blockade inhibits myogenic constriction of skeletal muscle resistance arterioles. Am J Physiol Heart Circ Physiol 289: H322–H329, 2005.[Abstract/Free Full Text]
  110. Martinez-Lemus LA, Hill MA, Bolz SS, Pohl U, Meininger GA. Acute mechanoadaptation of vascular smooth muscle cells in response to continuous arteriolar vasoconstriction: implications for functional remodeling. FASEB J 18: 708–710, 2004.[Abstract/Free Full Text]
  111. Martinez-Lemus LA, Wu X, Wilson E, Hill MA, Davis GE, Davis MJ, Meininger GA. Integrins as unique receptors for vascular control. J Vasc Res 40: 211–233, 2003.[CrossRef][Web of Science][Medline]
  112. Mathiassen ON, Buus NH, Sihm I, Thybo NK, Morn B, Schroeder AP, Thygesen K, Aalkjaer C, Lederballe O, Mulvany MJ, Christensen KL. Small artery structure is an independent predictor of cardiovascular events in essential hypertension. J Hypertens 25: 1021–1026, 2007.[Web of Science][Medline]
  113. Mehta D, Gunst SJ. Actin polymerization stimulated by contractile activation regulates force development in canine tracheal smooth muscle. J Physiol 519: 829–840, 1999.[Abstract/Free Full Text]
  114. Meininger GA, Harris PD, Joshua IG. Distributions of microvascular pressure in skeletal muscle of one- kidney, one clip, two-kidney, one clip, and deoxycorticosterone-salt hypertensive rats. Hypertension 6: 27–34, 1984.[Abstract/Free Full Text]
  115. Mills I, Fallon JT, Wrenn D, Sasken H, Gray W, Bier J, Levine D, Berman S, Gilson M, Gewirtz H. Adaptive responses of coronary circulation and myocardium to chronic reduction in perfusion pressure and flow. Am J Physiol Heart Circ Physiol 266: H447–H457, 1994.[Abstract/Free Full Text]
  116. Mogford JE, Davis GE, Meininger GA. RGDN peptide interaction with endothelial alpha5beta1 integrin causes sustained endothelin-dependent vasoconstriction of rat skeletal muscle arterioles. J Clin Invest 100: 1647–1653, 1997.[Web of Science][Medline]
  117. Mogford JE, Davis GE, Platts SH, Meininger GA. Vascular smooth muscle alpha v beta 3 integrin mediates arteriolar vasodilation in response to RGD peptides. Circ Res 79: 821–826, 1996.[Abstract/Free Full Text]
  118. Mulvany MJ. Small artery structure: time to take note? Am J Hypertens 20: 853–854, 2007.[CrossRef][Web of Science][Medline]
  119. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension 28: 505–506, 1996.[Web of Science][Medline]
  120. Na S, Meininger GA, Humphrey JD. A theoretical model for F-actin remodeling in vascular smooth muscle cells subjected to cyclic stretch. J Theor Biol 246: 87–99, 2007.[CrossRef][Web of Science][Medline]
  121. Na S, Trache A, Trzeciakowski J, Sun Z, Meininger GA, Humphrey JD. Time-dependent changes in smooth muscle cell stiffness and focal adhesion area in response to cyclic equibiaxial stretch. Ann Biomed Eng 36: 369–380, 2008.[CrossRef][Web of Science][Medline]
  122. New DI, Chesser AM, Thuraisingham RC, Yaqoob MM. Structural remodeling of resistance arteries in uremic hypertension. Kidney Int 65: 1818–1825, 2004.[CrossRef][Web of Science][Medline]
  123. Ogden K, Thompson JM, Hickner Z, Huang T, Tang DD, Watts SW. A new signaling paradigm for serotonin: use of Crk-associated substrate in arterial contraction. Am J Physiol Heart Circ Physiol 291: H2857–H2863, 2006.[Abstract/Free Full Text]
  124. Ohanian V, Gatfield K, Ohanian J. Role of the actin cytoskeleton in G-protein-coupled receptor activation of PYK2 and paxillin in vascular smooth muscle. Hypertension 46: 93–99, 2005.[Abstract/Free Full Text]
  125. Park JB, Schiffrin EL. Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. J Hypertens 19: 921–930, 2001.[CrossRef][Web of Science][Medline]
  126. Parker SB, Dobrian AD, Wade SS, Prewitt RL. AT(1) receptor inhibition does not reduce arterial wall hypertrophy or PDGF-A expression in renal hypertension. Am J Physiol Heart Circ Physiol 278: H613–H622, 2000.[Abstract/Free Full Text]
  127. Petit V, Thiery JP. Focal adhesions: structure and dynamics. Biol Cell 92: 477–494, 2000.[CrossRef][Web of Science][Medline]
  128. Pistea A, Bakker EN, Spaan JA, Hardeman MR, van Rooijen N, VanBavel E. Small artery remodeling and erythrocyte deformability in L-NAME-induced hypertension: role of transglutaminases. J Vasc Res 45: 10–18, 2008.[CrossRef][Web of Science][Medline]
  129. Pistea A, Bakker EN, Spaan JA, VanBavel E. Flow inhibits inward remodeling in cannulated porcine small coronary arteries. Am J Physiol Heart Circ Physiol 289: H2632–H2640, 2005.[Abstract/Free Full Text]
  130. Platts SH, Falcone JC, Holton WT, Hill MA, Meininger GA. Alteration of microtubule polymerization modulates arteriolar vasomotor tone. Am J Physiol Heart Circ Physiol 277: H100–H106, 1999.[Abstract/Free Full Text]
  131. Platts SH, Martinez-Lemus LA, Meininger GA. Microtubule-dependent regulation of vasomotor tone requires Rho-kinase. J Vasc Res 39: 173–182, 2002.[CrossRef][Web of Science][Medline]
  132. Porteri E, Rizzoni D, Mulvany MJ, De Ciuceis C, Sleiman I, Boari GE, Castellano M, Muiesan ML, Zani F, Rosei EA. Adrenergic mechanisms and remodeling of subcutaneous small resistance arteries in humans. J Hypertens 21: 2345–2352, 2003.[CrossRef][Medline]
  133. Pourageaud F, De Mey JG. Structural properties of rat mesenteric small arteries after 4-wk exposure to elevated or reduced blood flow. Am J Physiol Heart Circ Physiol 273: H1699–H1706, 1997.[Abstract/Free Full Text]
  134. Pourageaud F, De Mey JG. Vasomotor responses in chronically hyperperfused and hypoperfused rat mesenteric arteries. Am J Physiol Heart Circ Physiol 274: H1301–H1307, 1998.[Abstract/Free Full Text]
  135. Rasmussen H, Takuwa Y, Park S. Protein kinase C in the regulation of smooth muscle contraction. FASEB J 1: 177–185, 1987.[Abstract]
  136. Rembold CM. Force suppression and the cross-bridge cycle in swine carotid artery. Am J Physiol Cell Physiol 293: C1003–C1009, 2007.[Abstract/Free Full Text]
  137. Rembold CM, Tejani AD, Ripley ML, Han S. Paxillin phosphorylation, actin polymerization, noise temperature, and the sustained phase of swine carotid artery contraction. Am J Physiol Cell Physiol 293: C993–C1002, 2007.[Abstract/Free Full Text]
  138. Rhodin JAG. Architecture of the vessel wall. In: Handbook of Physiology. The Cardiovascular System. Vascular Smooth Muscle. Bethesda, MD: Am. Physiol. Soc., 1980, sect. 2, vol. II, chapt. 1, p. 1–32.
  139. Rizzoni D, Porteri E, Boari GE, De Ciuceis C, Sleiman I, Muiesan ML, Castellano M, Miclini M, Agabiti-Rosei E. Prognostic significance of small-artery structure in hypertension. Circulation 108: 2230–2235, 2003.[Abstract/Free Full Text]
  140. Rizzoni D, Porteri E, Giustina A, De Ciuceis C, Sleiman I, Boari GE, Castellano M, Muiesan ML, Bonadonna S, Burattin A, Cerudelli B, Agabiti-Rosei E. Acromegalic patients show the presence of hypertrophic remodeling of subcutaneous small resistance arteries. Hypertension 43: 561–565, 2004.[Abstract/Free Full Text]
  141. Rizzoni D, Porteri E, Piccoli A, Castellano M, Bettoni G, Muiesan ML, Pasini G, Guelfi D, Mulvany MJ, Agabiti Rosei E. Effects of losartan and enalapril on small artery structure in hypertensive rats. Hypertension 32: 305–310, 1998.[Abstract/Free Full Text]
  142. Saito SY, Hori M, Ozaki H, Karaki H. Cytochalasin D inhibits smooth muscle contraction by directly inhibiting contractile apparatus. J Smooth Muscle Res 32: 51–60, 1996.[Medline]
  143. Sakurada S, Okamoto H, Takuwa N, Sugimoto N, Takuwa Y. Rho activation in excitatory agonist-stimulated vascular smooth muscle. Am J Physiol Cell Physiol 281: C571–C578, 2001.[Abstract/Free Full Text]
  144. Sakurada S, Takuwa N, Sugimoto N, Wang Y, Seto M, Sasaki Y, Takuwa Y. Ca2+-dependent activation of Rho and Rho kinase in membrane depolarization-induced and receptor stimulation-induced vascular smooth muscle contraction. Circ Res 93: 548–556, 2003.[Abstract/Free Full Text]
  145. Schiffrin EL. Effects of antihypertensive drugs on vascular remodeling: do they predict outcome in response to antihypertensive therapy? Curr Opin Nephrol Hypertens 10: 617–624, 2001.[CrossRef][Web of Science][Medline]
  146. Schiffrin EL. Remodeling of resistance arteries in essential hypertension and effects of antihypertensive treatment. Am J Hypertens 17: 1192–1200, 2004.[CrossRef][Web of Science][Medline]
  147. Schiffrin EL, Lariviere R, Li JS, Sventek P, Touyz RM. Deoxycorticosterone acetate plus salt induces overexpression of vascular endothelin-1 and severe vascular hypertrophy in spontaneously hypertensive rats. Hypertension 25: 769–773, 1995.[Abstract/Free Full Text]
  148. Shaw L, Ahmed S, Austin C, Taggart MJ. Inhibitors of actin filament polymerisation attenuate force but not global intracellular calcium in isolated pressurised resistance arteries. J Vasc Res 40: 1–10, 2003.[CrossRef][Web of Science][Medline]
  149. Shibuya J, Ohyanagi M, Iwasaki T. Enhanced myogenic response in resistance small arteries from spontaneously hypertensive rats: relationship to the voltage-dependent calcium channel. Am J Hypertens 11: 767–773, 1998.[CrossRef][Web of Science][Medline]
  150. Short D. Morphology of the intestinal arterioles in chronic human hypertension. Br Heart J 28: 184–192, 1966.[Free Full Text]
  151. Sierevogel MJ, Pasterkamp G, Velema E, de Jaegere PP, de Smet BJ, Verheijen JH, de Kleijn DP, Borst C. Oral matrix metalloproteinase inhibition and arterial remodeling after balloon dilation: an intravascular ultrasound study in the pig. Circulation 103: 302–307, 2001.[Abstract/Free Full Text]
  152. Silver FH, Horvath I, Foran DJ. Viscoelasticity of the vessel wall: the role of collagen and elastic fibers. Crit Rev Biomed Eng 29: 279–301, 2001.[Web of Science][Medline]
  153. Simon G, Csiky B. Effect of neonatal sympathectomy on the development of structural vascular changes in angiotensin II-treated rats. J Hypertens 16: 77–84, 1998.[CrossRef][Web of Science][Medline]
  154. Simon G, Jaeckel M, Illyes G. Altered structure and distensibility of arteries in salt-fed rats. J Hypertens 21: 137–143, 2003.[CrossRef][Web of Science][Medline]
  155. Somlyo AP, Somlyo AV. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 83: 1325–1358, 2003.[Abstract/Free Full Text]
  156. Song W, Ergul A. Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: relation to vessel size. Cardiovasc Diabetol 5: 3, 2006.[CrossRef][Medline]
  157. Sorop O, Bakker EN, Pistea A, Spaan JA, VanBavel E. Calcium channel blockade prevents pressure-dependent inward remodeling in isolated subendocardial resistance vessels. Am J Physiol Heart Circ Physiol 291: H1236–H1245, 2006.[Abstract/Free Full Text]
  158. Sorop O, Merkus D, de Beer VJ, Houweling B, Pistea A, McFalls EO, Boomsma F, van Beusekom HM, van der Giessen WJ, VanBavel E, Duncker DJ. Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis. Circ Res 102: 795–803, 2008.[Abstract/Free Full Text]
  159. Sun Z, Martinez-Lemus LA, Hill MA, Meininger G. Extracellular matrix-specific focal adhesions in vascular smooth muscle produce mechanically active adhesion sites. Am J Physiol Cell Physiol 295: C268–C278, 2008.[Abstract/Free Full Text]
  160. Sun Z, Martinez-Lemus LA, Trache A, Trzeciakowski JP, Davis GE, Pohl U, Meininger GA. Mechanical properties of the interaction between fibronectin and alpha5beta1-integrin on vascular smooth muscle cells studied using atomic force microscopy. Am J Physiol Heart Circ Physiol 289: H2526–H2535, 2005.[Abstract/Free Full Text]
  161. Tang D, Mehta D, Gunst SJ. Mechanosensitive tyrosine phosphorylation of paxillin and focal adhesion kinase in tracheal smooth muscle. Am J Physiol Cell Physiol 276: C250–C258, 1999.[Abstract/Free Full Text]
  162. Tang DD. Intermediate filaments in smooth muscle. Am J Physiol Cell Physiol 294: C869–C878, 2008.[Abstract/Free Full Text]
  163. Tang DD, Anfinogenova Y. Physiologic properties and regulation of the actin cytoskeleton in vascular smooth muscle. J Cardiovasc Pharmacol Ther 13: 130–140, 2008.[Abstract/Free Full Text]
  164. Tang DD, Gunst SJ. The small GTPase Cdc42 regulates actin polymerization and tension development during contractile stimulation of smooth muscle. J Biol Chem 279: 51722–51728, 2004.[Abstract/Free Full Text]
  165. Tang DD, Zhang W, Gunst SJ. The adapter protein CrkII regulates neuronal Wiskott-Aldrich syndrome protein, actin polymerization, and tension development during contractile stimulation of smooth muscle. J Biol Chem 280: 23380–23389, 2005.[Abstract/Free Full Text]
  166. Touyz RM. The role of angiotensin II in regulating vascular structural and functional changes in hypertension. Curr Hypertens Rep 5: 155–164, 2003.[Web of Science][Medline]
  167. Tulis DA, Unthank JL, Prewitt RL. Flow-induced arterial remodeling in rat mesenteric vasculature. Am J Physiol Heart Circ Physiol 274: H874–H882, 1998.[Abstract/Free Full Text]
  168. Tuttle JL, Nachreiner RD, Bhuller AS, Condict KW, Connors BA, Herring BP, Dalsing MC, Unthank JL. Shear level influences resistance artery remodeling: wall dimensions, cell density, and eNOS expression. Am J Physiol Heart Circ Physiol 281: H1380–H1389, 2001.[Abstract/Free Full Text]
  169. Unthank JL, Fath SW, Burkhart HM, Miller SC, Dalsing MC. Wall remodeling during luminal expansion of mesenteric arterial collaterals in the rat. Circ Res 79: 1015–1023, 1996.[Abstract/Free Full Text]
  170. VanBavel E, Siersma P, Spaan JA. Elasticity of passive blood vessels: a new concept. Am J Physiol Heart Circ Physiol 285: H1986–H2000, 2003.[Abstract/Free Full Text]
  171. Vouyouka AG, Pfeiffer BJ, Liem TK, Taylor TA, Mudaliar J, Phillips CL. The role of type I collagen in aortic wall strength with a homotrimeric. J Vasc Surg 33: 1263–1270, 2001.[CrossRef][Web of Science][Medline]
  172. Walsh MP, Susnjar M, Deng J, Sutherland C, Kiss E, Wilson DP. Phosphorylation of the protein phosphatase type 1 inhibitor protein CPI-17 by protein kinase C. Meth Mol Biol 365: 209–223, 2007.[Medline]
  173. Wesselman JP, Kuijs R, Hermans JJ, Janssen GM, Fazzi GE, van Essen H, Evelo CT, Struijker-Boudier HA, De Mey JG. Role of the Rhoa/Rho kinase system in flow-related remodeling of rat mesenteric small arteries in vivo. J Vasc Res 41: 277–290, 2004.[CrossRef][Web of Science][Medline]
  174. Wier WG, Morgan KG. Alpha1-adrenergic signaling mechanisms in contraction of resistance arteries. Rev Physiol Biochem Pharmacol 150: 91–139, 2003.[Medline]
  175. Wilson DP, Sutherland C, Borman MA, Deng JT, Macdonald JA, Walsh MP. Integrin-linked kinase is responsible for Ca2+-independent myosin diphosphorylation and contraction of vascular smooth muscle. Biochem J 392: 641–648, 2005.[CrossRef][Web of Science][Medline]
  176. Wright G, Hurn E. Cytochalasin inhibition of slow tension increase in rat aortic rings. Am J Physiol Heart Circ Physiol 267: H1437–H1446, 1994.[Abstract/Free Full Text]
  177. Wu X, Davis GE, Meininger GA, Wilson E, Davis MJ. Regulation of the L-type calcium channel by alpha 5beta 1 integrin requires signaling between focal adhesion proteins. J Biol Chem 276: 30285–30292, 2001.[Abstract/Free Full Text]
  178. Wu X, Mogford JE, Platts SH, Davis GE, Meininger GA, Davis MJ. Modulation of calcium current in arteriolar smooth muscle by alphav beta3 and alpha5 beta1 integrin ligands. J Cell Biol 143: 241–252, 1998.[Abstract/Free Full Text]
  179. Yeon DS, Kim JS, Ahn DS, Kwon SC, Kang BS, Morgan KG, Lee YH. Role of protein kinase C- or RhoA-induced Ca2+ sensitization in stretch-induced myogenic tone. Cardiovasc Res 53: 431–438, 2002.[Abstract/Free Full Text]
  180. Zhang W, Gunst SJ. Dynamic association between alpha-actinin and beta-integrin regulates contraction of canine tracheal smooth muscle. J Physiol 572: 659–676, 2006.[Abstract/Free Full Text]
  181. Zhang W, Gunst SJ. Interactions of airway smooth muscle cells with their tissue matrix: implications for contraction. Proc Am Thorac Soc 5: 32–39, 2008.[Abstract/Free Full Text]
  182. Zhang W, Wu Y, Du L, Tang DD, Gunst SJ. Activation of the Arp2/3 complex by N-WASp is required for actin polymerization and contraction in smooth muscle. Am J Physiol Cell Physiol 288: C1145–C1160, 2005.[Abstract/Free Full Text]
  183. Zhang W, Wu Y, Wu C, Gunst SJ. Integrin-linked kinase regulates N-WASp-mediated actin polymerization and tension development in tracheal smooth muscle. J Biol Chem 282: 34568–34580, 2007.[Abstract/Free Full Text]
  184. Zhou MS, Jaimes EA, Raij L. Vascular but not cardiac remodeling is associated with superoxide production in angiotensin II hypertension. J Hypertens 23: 1737–1743, 2005.[Web of Science][Medline]



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