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News Physiol Sci 17: 197-201, 2002; doi:10.1152/nips.01395.2001
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News in Physiological Sciences, Vol. 17, No. 5, 197-201, October 2002
© 2002 Int. Union Physiol. Sci./Am. Physiol. Soc.

Angioadaptation: Keeping the Vascular System in Shape

Andreas Zakrzewicz1, Timothy W. Secomb3 and Axel R. Pries1,2

1 Department of Physiology, Freie Universität Berlin, D-14195 Berlin;
2 German Heart Center Berlin, D-13353 Berlin, Germany; and
3 Department of Physiology, University of Arizona, Tucson, Arizona 85724-5051

   Abstract
 
The development and maintenance of the vascular system requires not only the formation of new vessels (vasculogenesis, angiogenesis) but also the continuous adjustment of vessel and network structures in response to functional needs. This "angioadaptation" depends on the interplay of vascular responses to growth factors, to the metabolic status of the tissue, and to hemodynamic forces exerted by the flowing blood.


   Introduction
Top
 Introduction
Roles of metabolic and...
 Molecular mechanisms of...
 Angioadaptation in normal and...
 References
 
Development of the vascular system is initiated in the embryo. During this initial stage, termed vasculogenesis (15), vessels are generated from bipotent precursor cells, the hemangioblasts. Basic fibroblast growth factor (bFGF) then stimulates expression of the vascular endothelial growth factor (VEGF) receptor-2, which induces differentiation to angioblasts and to endothelial cells. The endothelial cells express VEGF receptor-1, which supports the generation of tubular structures, leading to a mesh-like primary vascular plexus.

Formation of a functional vascular system from this vascular mesh requires addition of new segments ("angiogenesis"), structural alteration of existing segments ("remodeling"), and elimination of redundant segments ("pruning") (15). Two basic modes of angiogenesis have been identified. In vessel splitting ("intussusception"), endothelial cells from opposite sides of the capillary protrude into the lumen and fuse, creating a pillar across the capillary. This pillar elongates in the direction of the vessel axis, leading to the generation of two parallel capillaries. In vessel "sprouting," the extracellular matrix of the existing vessel wall is degraded by proteolytic enzymes. Then endothelial cells proliferate and migrate, forming a solid bud that develops into a hollow capillary sprout. If this sprout establishes contact with another existing vessel, the new pathway is transformed into a stable vessel by recruitment of pericytes that reinforce the vessel wall.

The mechanisms controlling these structural changes vary according to the developmental stage of the organism. During vasculogenesis, embryological mechanisms of pattern formation dictate the locations of the primary conduits, which will later become the major arteries and veins (6). This process takes place in the absence of any stimuli reflecting the functional status of the network, since blood flow is absent and oxygen and nutrients are externally supplied. In contrast, much evidence shows that feedback signals, in the form of stimuli that depend on the functional performance of the system, play a major role in determining structural changes during postnatal development and in mature individuals. As discussed below, vessels respond to physical forces generated by blood flow and to levels of metabolites, especially oxygen. This ability of the vasculature to respond to ambient conditions is prominent in situations such as growth, functional changes accompanying training or the menstrual cycle, inflammation and wound healing, tumor vascularization, and retinopathy. Angiogenesis in such situations can be fast and dramatic. Even if tissue function changes slowly, however, vascular network structure must be matched to tissue requirements. Therefore, the vasculature is in a continuous state of dynamic adaptation, with changes in wall structure and diameter and addition or loss of vascular segments occurring as needed. We propose the term "angioadaptation" to describe this set of processes (Fig. 1Go).



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  		FIGURE 1. Processes of angioadaptation, i.e., structural adaptation of vascular networks, involving addition or loss of vascular segments and changes in wall structure and diameter. Changes in phenotype (arteriolar, capillary, or venular) or other properties may also be involved.

 

   Roles of metabolic and hemodynamic stimuli in angioadaptation
Top
 Introduction
 Roles of metabolic and...
Molecular mechanisms of...
 Angioadaptation in normal and...
 References
 
The distance that oxygen can diffuse into an oxygen-consuming tissue is very short, typically in the range of 20–100 µm. Therefore, the need for an adequate supply of oxygen to all parts of the tissue is a stringent functional requirement that must be satisfied by the structure of the vascular system. It is natural to consider whether the partial pressure of oxygen (PO2) is itself a stimulus for angioadaptation. Evidence suggests that this is indeed the case. Hypoxia-inducible transcription factors have been shown to regulate the expression of VEGF (20), which has effects on many of the successive steps of angiogenesis (3). Hypoxia has been shown to induce the expression of angiopoietin-2 (Ang-2) (11), which also plays an important role in regulating vascular development and regression (4,10).

However, structural adaptation in response to oxygen alone would not lead to functionally adequate vascular systems. For example, if the region supplied by an arteriole becomes hypoxic as a result of increased local oxygen consumption or some other perturbation, a structural increase in arteriolar diameter may be needed so that the arteriole can deliver adequate flow, even if it is in a well-oxygenated region. Signals other than oxygen must be involved. Blood vessels are known to respond to hemodynamic forces, i.e., shear stress acting on the endothelial surface resulting from blood flow and circumferential stress in the vessel wall resulting from transmural pressure. In general, increased wall shear stress leads to structural increases in luminal diameters (8), whereas increased circumferential stress leads to the opposite effect (5). (It is noteworthy that these structural responses are parallel to acute responses resulting from changes in smooth muscle tone elicited by the same stimuli.) The response to wall shear stress provides a means to coordinate diameter changes of proximal vessels with those of distal vessels. If a distal vessel increases in diameter, the resulting increase in flow causes increased shear stress in proximal vessels, also causing their diameters to increase.

Theoretical simulations can be used to predict the angioadaptation of vascular networks resulting from the combined effects of responses to metabolic and hemodynamic stimuli. Such a model for adaptive changes in vessel diameters (13,14) was used to predict distributions of diameters and blood flow velocities. Predictions were compared with observations in the rat mesentery. Functionally adequate networks in good agreement with observations could be obtained only if it was assumed that each segment in the network responds to local PO2, wall shear stress, and intravascular pressure and, furthermore, that mechanisms for information transfer are present, such that each proximal segment receives propagated stimuli that depend on the number and metabolic state of the distal segments supplied or drained by that segment. Possible mechanisms for this information transfer include downstream-convective transport of vasoactive metabolites (13) and upstream-conducted responses involving changes in vascular cell membrane potential (19).

Hemodynamic variables show a striking degree of heterogeneity in the microcirculation. For example, wall shear stress shows an overall decline with decreasing intravascular pressure, from ~100 dyn/cm2 in the feeding arterioles to ~10 dyn/cm2 in the draining venules. Individual values vary by about two orders of magnitude at any given pressure (Fig. 2Go). The presence of multiple interacting angioadaptive stimuli provides a likely explanation for this heterogeneity. For example, if vascular diameters varied only in response to departures of wall shear stress from a fixed set point, all segments would be expected to achieve an equilibrium diameter at the same shear stress. A combined response to shear and pressure would lead to a unique functional dependence of shear stress on pressure. If, however, vessels respond simultaneously not only to hemodynamic stimuli but also to metabolic and propagated stimuli, they would be expected to achieve widely varying levels of shear stress. This concept is supported by theoretical simulations (13).



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  		FIGURE 2. Distribution of wall shear stress in microvascular vessel segments in the rat mesentery. Vascular networks were scanned by intravital microscopy. From measured data (vessel diameter and length, network topology), pressure and wall shear stress were calculated for all vessel segments. A: two-dimensional map of network (~4 x 6 mm). Shear stress is higher in feeding arterioles (red arrow) than in draining venules (blue arrow). B: scatter plot of wall shear stress vs. pressure. Wall shear stress varies by 1–2 orders of magnitude for all vessel categories (ART, arteriole; CAP, capillary; VEN, vein).

 

   Molecular mechanisms of angioadaptation
Top
 Introduction
 Roles of metabolic and...
 Molecular mechanisms of...
Angioadaptation in normal and...
 References
 
A thorough description of the molecular mechanisms of angioadaptation will require identifying the processes by which wall shear stress, circumferential stress, PO2, and other stimuli are sensed and the signaling pathways by which responses to these stimuli lead to structural changes, including angiogenesis and remodeling. Within recent years, detailed information about several steps in this process has been obtained, and a picture is emerging of how different molecular pathways may be coordinated according to the physiological needs of the tissue.

Over 20 activators and a similar number of inhibitors are involved in angiogenesis (2). Some can be identified with specific angiogenetic steps. Sprouting is preceded by an increase in vessel diameter mediated in part by the vasoactive substance nitric oxide. Then VEGF increases the permeability of the vessel wall and plasma proteins leak into the interstitial space, generating guiding structures for the migrating endothelial cells. The endothelial tyrosine kinase receptor Tie-2 is blocked by its endogenous antagonist Ang-2. This leads to a separation of smooth muscle cells from the vascular wall and thus to a further loosening of the wall, making migration of endothelial cells easier. Over 20 different metalloproteinases are available to generate space for emigrating endothelial cells by degrading the extracellular matrix. This process also releases a number of growth factors (bFGF, VEGF, and IGF-I) bound to components of the extracellular matrix. Additional proteinases such as urokinase plasminogen activator are involved, especially in the heart, in softening the tissue.

Stimulated by VEGF, bFGF, Ang-2, and their receptors, endothelial cells exhibit substantial growth and proliferation. In the generation of a solid endothelial bud, angiopoietin-1 (Ang-1), which exerts a chemotactic effect on endothelial cells by activating its receptor Tie-2, as well as cellular adhesion molecules, especially integrins, play a central role. Integrins ({alpha}5ß1, {alpha}vß3) are also involved in the following generation of a vascular lumen, transforming the initial bud into a capillary sprout. The luminal width can be increased by shorter splice variants of VEGF (VEGF121, VEGF165) as well as Ang-1 and be decreased by the longer VEGF variant VEGF189. Platelet-derived growth factor (PDGF)-B and the activation of Tie-2 then lead to the recruitment of pericytes and/or smooth muscle cells and thus to the generation of a mature vessel wall. In addition, the steps of angiogenesis are subject to continuous control by endogenous inhibitors. For example, the generation of a vascular lumen can be suppressed by thrombospondin-1.

The sensing of wall shear stress by the vessel walls likely involves changes in cytoskeletal structure, metabolism, and gene expression (12). Mechanosensitive cation channels, G protein-coupled receptors, and cellular structures involved in bearing the shear forces, such as the cytoskeleton and intracellular adhesion molecules, have been proposed as sensors. The subsequent signal transduction involves the ras-raf and ras-JNK pathways. Protein kinase C is also activated and leads to an activation of the transcription factor NF-{kappa}B. Other transcription factors that appear to be regulated by wall shear stress include activator protein-1 and members of the Ets family, Ets-1 and Elk-1. The endothelial receptor tyrosine kinases VEGF-R1, VEGF-R2, Tie-1, and Tie-2 are among the genes regulated by Ets . It is thus very likely that Ets family members play a significant role in the regulation of angiogenesis (9) and are involved in the adaptation of blood vessels to wall shear stress. The transcription factor Elk-1 induces the expression of the early response gene Egr-1, which increases the transcription of the growth factor PDGF-A by interaction with a shear stress response element in the promoter region of the PDGF-A gene (7,17). In this way, smooth muscle cells are recruited into the vessel wall, supporting its arterialization.

Given the many factors involved, the mechanisms that determine the structural responses of blood vessels to the combined effects of changes in PO2 and wall shear stress are likely to be complex. An example and possible prototype for the interaction of different stimuli is the scheme shown in Fig. 3Go. Hanahan (4) proposed that the combined effects of the VEGF and Ang-2/Tie-2 systems can produce several distinctly different reaction patterns, including stabilization, angiogenesis, and regression. These reactions are indicated in Fig. 3Go, in combination with the effects of oxygen level and flow stress on VEGF and Ang-2 expression. In this scheme, the structural reactions correspond to expected physiological responses to relative levels of oxygen and blood flow.



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  		FIGURE 3. Schematic representation of operation of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)/Tie-2 systems in angioadaptation in response to wall shear stress and partial pressure of oxygen (PO2). A: under normal conditions, high PO2 ensures low VEGF expression. Blood flow suppresses expression of shear-regulated genes, including Ang-2 (1). The tyrosine kinase receptor Tie-2 is activated by its constitutively expressed ligand Ang-1 and stabilizes the vessel wall. This corresponds to a mature, quiescent blood vessel. B: hypoxic conditions combined with low flow induce expression of both VEGF and Ang-2 (11). Ang-2 displaces Ang-1 from their common receptor Tie-2, which is thus inactivated. This removes the stabilizing effect of Tie-2 on the vessel wall, allowing VEGF to fully exert its angiogenetic potential. Such a low-flow, hypoxic situation requires vascular proliferation, leading to enlargement of existing vessels and/or formation of new vessels. C: under normoxic, low-flow conditions, VEGF expression is low but Ang-2 expression is increased, again destabilizing the vessel wall. In this case, regression rather than proliferation is to be expected. Such conditions characterize redundant vessels, which are underperfused in a well-oxygenated environment and which can be removed by this pruning mechanism. A similar situation is seen during involution of the corpus luteum. R, receptor. Figure modified from Ref. 4.

 

   Angioadaptation in normal and pathological states
Top
 Introduction
 Roles of metabolic and...
 Molecular mechanisms of...
 Angioadaptation in normal and...
References
 
Although far from complete, the concepts outlined above provide a framework for interpreting changes in vascular structure occurring in several different conditions. For a first example, we consider the response of an existing vessel to a nearby region with inadequate vascular supply (Fig. 4AGo). The resulting hypoxia induces expression of VEGF and Ang-2. VEGF diffusing to the existing vessel causes formation of capillary sprouts, which grow toward the hypoxic region. In a sprout that has not made contact with a preexisting vessel, the wall shear stress is negligible. Under these conditions, Tie-2 is likely blocked by Ang-2, loosening the vessel wall and allowing the endothelial cells to react strongly to VEGF. Gas-3 (which can arrest the cell cycle) and the angiogenesis inhibitor METH-1 are suppressed, creating optimal conditions for endothelial proliferation and sprouting. Sprouts that connect to other vessels, forming a flow pathway, are stabilized through the activation of Tie-2 (Fig. 3AGo). Once the formerly hypoxic tissue is oxygenated, those new vessels that have not formed part of a flow pathway, and are now redundant, are eliminated by pruning (Fig. 3CGo). In this way, the combined effects of angioadaptive responses to PO2 and flow can result in a functionally adequate vascular supply to the formerly hypoxic region.



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  		FIGURE 4. Examples of angioadaptation. A: capillary sprouting, e.g., induced by a VEGF released from a hypoxic tissue. A similar process leads to the vascularization of a tumor from surrounding normal tissue. B: collateralization induced by arterial occlusion. The altered hemodynamic situation leads to increased shear stress in existing narrow connections to neighboring vessels, which then increase in diameter, despite being in a well-oxygenated environment.

 
For a second example, we consider what happens when a small artery supplying a given tissue region is occluded (Fig. 4BGo). Frequently, microvascular connections to another artery (arcades) can provide an alternative pathway for blood flow to the tissue, although this pathway may be too narrow to supply the tissue. Blood flow rate and wall shear stress in this pathway are greatly increased, because it is flowing into a low-pressure region. Data from in vitro studies suggest that Tie-2 is massively induced in this situation, leading to enlargement and reinforcement of the vessel. In this process, smooth muscle cells are recruited into the growing vessel wall under the influence of PDGF, which is also upregulated by shear. Activation of Bcl-2 has an additional antiapoptotic effect, and the increased production of the antiangiogenetic factor METH-1 suppresses local generation of capillary sprouts. This process has been analyzed in the context of generation of collaterals upon occlusion of coronary vessels and has been termed "arterialization" (16). The distinctive feature of this process is that a substantial increase in wall shear stress can trigger vascular growth even in a well-oxygenated environment.

For a third example, we consider the vascular beds of tumors, which are characteristically disorganized, with irregular diameters, very short arteriovenous shunt connections, and long capillary loops. In spite of the high vascular density, oxygen delivery to the tissue is insufficient, resulting in a large heterogeneity of local tissue oxygenation (18). These features strongly suggest that the normal balance between the mechanisms controlling angioadaptation is disturbed in tumors. High levels of proangiogenetic factors, notably VEGF, are typical for tumors, but mechanisms for stabilizing functional vessels and pruning redundant vessels seem to be lacking.

In conclusion, the functional demands placed on the vascular system can only be met efficiently if its structure and blood flow distribution are closely matched to the demands. To this end, the processes of angioadaptation are responsible for keeping the vascular system "in shape." Structural responses to PO2, wall shear stress, and intravascular pressure are required, along with propagated responses. The molecular mechanisms underlying these responses are beginning to be understood. Improved understanding of angioadaptation could lead to development of new therapeutic approaches. Future progress will require not only investigation of molecular and cellular mechanisms but also network-level studies that show how these mechanisms are integrated in a physiological context.


   Acknowledgments
 
This work was supported by National Heart, Lung, and Blood InstituteGrant HL-34555 and Deutsche Forschungsgemeinschaft Pr 271/5-4; Za 184/1-4.


   References
Top
 Introduction
 Roles of metabolic and...
 Molecular mechanisms of...
 Angioadaptation in normal and...
 References
 

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