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REVIEW

Microvascular Dysfunction in Obesity: A Potential Mechanism in the Pathogenesis of Obesity-Associated Insulin Resistance and Hypertension

Amy M. Jonk¹, Alfons J. H. M. Houben¹, Renate T. de Jongh², Erik H. Serné², Nicoloaas C. Schaper¹ and Coen D. A. Stehouwer¹

¹ Department of Internal Medicine, University Hospital Maastricht, and Cardiovascular Research Institute Maastricht, Maastricht; and
² Department of Internal Medicine, VU Medical Center, Amsterdam, The Netherlands, csteh{at}sint.azm.nl

	Abstract

 
Obesity is an important risk factor for insulin resistance and hypertension and plays a central role in the metabolic syndrome. Insight into the pathophysiology of this syndrome may lead to new treatments. This paper has reviewed the evidence for an important role for the microcirculation as a possible link between obesity, insulin resistance and hypertension.

	Introduction

Top Introduction Microcirculation (Definition and... Microvascular Dysfunction in... Microvascular Dysfunction and... Microvascular Dysfunction and... Possible Mechanisms for Obesity... Conclusion References

 
The clustering of cardiovascular risk factors, including obesity and central fat distribution, hypertension, insulin resistance, dyslipidaemia, and proinflammatory and prothrombotic factors, has been recognized for many years and is often referred to as the metabolic syndrome (1, 47). Abdominal obesity is considered to play a central role in this syndrome and is a major risk factor for chronic diseases such as Type 2 diabetes mellitus and cardiovascular disease (49, 88). The incidence of obesity is progressively increasing worldwide and has reached epidemic proportions in several countries (37). Consequently, the prevalence of obesity-related disorders, such as insulin resistance and hypertension, is also increasing at an alarming rate. Although this is well recognized, the underlying mechanisms of obesity and obesity-related disorders remain relatively poorly understood. Unraveling these mechanisms is very important because it may lead to the development of therapeutic strategies that target the development of obesity-associated clinical disorders and, eventually, the development of Type 2 diabetes mellitus and cardiovascular disease.

Microvascular dysfunction may affect both peripheral vascular resistance (5, 75) and insulin-mediated glucose disposal (19, 92, 94, 117), thereby contributing to hypertension and insulin resistance, respectively. Recently, it has become clear that obesity is characterized by microvascular alterations (3, 29, 94). Therefore, we suggest that obesity may be a primary cause of microvascular dysfunction resulting in changes in pressure and flow patterns and, consequently, obesity-related hypertension and insulin resistance.

	Microcirculation (Definition and Functions)

Top Introduction Microcirculation (Definition and... Microvascular Dysfunction in... Microvascular Dysfunction and... Microvascular Dysfunction and... Possible Mechanisms for Obesity... Conclusion References

 
The microcirculation is widely taken to encompass vessels <150 µm in diameter. It therefore includes arterioles, capillaries, and venules. Nowadays, a definition based on arterial vessel physiology rather than diameter or structure has been proposed, depending on the response of the isolated vessel to increased internal pressure. By this definition, all vessels that respond to increasing pressure by a myogenic reduction in lumen diameter would be considered part of the microcirculation. Such a definition would include the smallest arteries and arterioles in the microcirculation in addition to capillaries and venules (68).

A primary function of the microcirculation is to optimize the delivery of nutrients and removal of waste products from all cells of the body in response to variations in demand (113). A second important function is to avoid large fluctuations in hydrostatic pressure at the level of the capillaries that otherwise would impair capillary exchange. Finally, it is at the level of the microcirculation that a substantial proportion of the drop in hydrostatic pressure occurs. The microcirculation is, therefore, extremely important in determining the overall peripheral resistance (68).

In normal conditions, systemic, regional, and local metabolic and myogenic autoregulatory mechanisms ensure adequate progress of these microcirculatory functions (60, 113). In pathological conditions (e.g., obesity), however, the loss of such mechanisms results in the development of microvascular dysfunction.

	Microvascular Dysfunction in Obesity

Top Introduction Microcirculation (Definition and... Microvascular Dysfunction in... Microvascular Dysfunction and... Microvascular Dysfunction and... Possible Mechanisms for Obesity... Conclusion References

 
Evidence from several studies indicates that obesity impairs microvascular function in several ways. First, impairments of endothelial function of different microvascular structures have been demonstrated in obesity. Obese subjects showed blunted vasodilation in response to classic endothelium-dependent vasodilators in skin and resistance arteries (24, 29, 101). In addition, obese individuals showed diminished vasodilator function of resistance vessels and capillary recruitment to reactive hyperemia (6, 24, 29, 41) and shear stress (6). Of great interest are observations on insulin-mediated control of tissue perfusion. Over a decade ago, Laakso et al. (64) drew attention to the decreased sensitivity of resistance vessels to insulin-induced endothelium-dependent vasodilation in obese individuals. Others have confirmed this observation in the microcirculation of the skin, using nailfold capillairoscopy (29). In addition to abolished insulin-induced vasodilation in resistance vessels, impaired microvascular recruitment during hyperinsulinemia has also been demonstrated (29). The latter is in good accordance with regard to microvascular recruitment in skeletal muscle. Wallis et al. (117) revealed impaired muscle microvascular action of insulin in obese rats, whereas Clerk et al. (21) were the first to demonstrate this in human obesity. In fact, measures of body fatness are strongly related to skin microvascular function even in lean individuals (27, 94). Second, in addition to these functional changes, structural impairments of the microvasculature have been demonstrated in obesity. The skeletal muscle circulation of obese Zucker rats shows decreased capillary density, so-called rarefaction (40, 42), and structural remodeling (103). Recent studies of obese individuals have also demonstrated this capillary rarefaction in human skeletal muscle (46, 107). There is convincing evidence that this reduction in microvessel density in obesity may be most accurately predicted by the reduced bioavailability of vasodilative agents (i.e., endothelial dysfunction) in obesity. However, the mechanisms through which this endothelial dysfunction-related reduction in skeletal muscle microvessel density evolves have not been fully elucidated (43). Some studies suggest that insulin, acting on the insulin and IGF receptors, in concert with angiotensin II (AngII) stimulates vascular remodeling (see also remodeling in hypertension below) (51).

In accord with a causal role for obesity in the pathogenesis of endothelial dysfunction, weight loss was found to improve endothelial function (131). It can be concluded that a clear association between obesity and microvascular dysfunction, possibly via the endothelium, in different tissues has been established.

	Microvascular Dysfunction and Hypertension

Top Introduction Microcirculation (Definition and... Microvascular Dysfunction in... Microvascular Dysfunction and... Microvascular Dysfunction and... Possible Mechanisms for Obesity... Conclusion References

 
In most forms of hypertension, cardiac output is close to normal, and the peripheral vascular resistance is increased in proportion to the increase in blood pressure. Since the major drop in hydrostatic pressure occurs in precapillary vessels ranging from 300 to 10 µm in diameter, i.e., the smallest arteries and arterioles, these vessels represent the principal site of the increased resistance in hypertension (68).

Hypertension is characterized by functional as well as structural changes in this microvasculature (68). First, the mechanisms regulating vasomotor tone may be abnormal, leading to enhanced vasoconstriction or reduced vasodilatation (55). Second, decreases in arteriolar diameters and increases in the wall-to-lumen ratio of small arteries have been demonstrated (55, 68, 104). Third, a reduction in the density (rarefaction) of arterioles, venules, and capillaries can be observed in different vascular beds (55, 56, 92, 104). Since the Hagen-Poiseille’s law shows that the resistance of a blood vessel is related to the inverse of the fourth power of vessel diameter, it can be appreciated that small reductions in diameter have significant consequences for vascular resistance (104).

It has been known for many years that increased wall-to-lumen ratio and microvascular rarefaction can be viewed as a result of increased vascular pressure. Among the factors that initiate this remodeling are endothelial dysfunction, changed blood flow, and increased transmural pressure. Since the endothelium serves as a pressure sensor and integrates signals to the underlying vascular smooth muscle cells, it plays an important role in this remodeling process. In addition, an increasing number of studies have shown that AngII is an important factor that stimulates vascular remodeling. Via multiple signalling pathways, AngII induces synthesis of growth factors and pro-inflammatory mediators, which lead to vascular injury and structural remodeling (109).

Besides being the consequence of hypertension, there is also evidence that these microvascular abnormalities may precede the elevation in blood pressure. A smaller retinal arteriolar diameter has been shown to prospectively predict the development of hypertension (57, 122). With regard to rarefaction, Le Noble et al. (67) found a structural rarefaction of capillaries and small arterioles in muscle of spontaneously hypertensive rats even in the absence of a substantial elevation in blood pressure. Human studies have demonstrated that patients with mild borderline primary hypertension showed as much skin capillary rarefaction as those with established hypertension (5). In addition, impaired microvascular vasodilation and capillary rarefaction were associated with a familial predisposition to essential hypertension (75). Furthermore, capillary density has been found to correlate inversely with blood pressure in hypertensive, normotensive lean, and normotensive obese subjects (29, 92, 94).

Thus microvascular abnormalities in obesity may contribute to the development of hypertension. Furthermore, a "vicious cycle" may exist in which the microcirculation maintains or even amplifies increased blood pressure in obesity.

	Microvascular Dysfunction and Insulin Resistance

Top Introduction Microcirculation (Definition and... Microvascular Dysfunction in... Microvascular Dysfunction and... Microvascular Dysfunction and... Possible Mechanisms for Obesity... Conclusion References

 
Insulin resistance is typically defined as decreased sensitivity for insulin-mediated glucose disposal. A major action of insulin in muscle and adipose tissue involves translocation of the insulin-responsive glucose transporter (GLUT4) to the cell surface, leading to glucose uptake in peripheral tissues. This requires phosphatidylinositol (PI3)-kinase-dependent signaling pathways (63).

In addition to this metabolic action, insulin has two discrete actions on the arterial vasculature to promote the delivery of insulin and glucose to skeletal muscles. In the 1990s, Baron and colleagues were the first to report insulin’s ability to vasodilate resistance vessels and consequently increase total skeletal muscle blood flow (8, 9). It was demonstrated that this increase in bulk blood flow was paralleled by an increase in insulin-mediated glucose uptake (11, 64).

Although several studies have confirmed this vascular action of insulin (15, 25, 105), some studies have failed to observe changes in total flow with insulin (19). Part of this discrepancy can be explained by subject factors as limb muscularity and physiological fitness. However, the duration and dose of the insulin infusion seems also to be important (123). In most studies, insulin-induced increases in total limb blood flow are only observed using supra-physiological doses of insulin or after several hours delay when physiological concentrations are used (128). Moreover, insulin-mediated changes in glucose uptake often precede insulin-mediated changes in leg blood flow, and studies during hyperinsulinemia and manipulation of total limb blood flow with different vasodilators have shown that total limb blood flow can be increased without any changes in insulin-mediated glucose uptake. As a consequence, the physiological importance, in stimulating glucose uptake, of insulin’s ability to increase total blood flow is doubtful (128).

Besides these actions on resistance vessels, insulin induces a second vascular action further down the arterial tree, termed functional capillary recruitment. By reducing precapillary arteriolar tone and/or altering arteriolar vasomotion, insulin redirects blood flow within the microvascular bed from non-nutritive to nutritive vessels, with a resultant increase in the overall number of perfused capillaries. Given that the nutritive capillary bed is directly involved in nutrient delivery to muscles, an increase in blood volume of the nutritive capillary bed directly enhances access of glucose and insulin to muscle tissue (19, 63).

Insulin-induced functionally capillary recruitment has been shown to require physiological concentrations of insulin with a time course that approximates the time course for insulin-mediated glucose uptake in skeletal muscle (63, 115, 123). Rattigan et al. (87) were the first to report this insulin-mediated capillary recruitment within the skeletal muscle of a rat’s hind limb. In subsequent in vivo rat studies, this insulin-induced effect on capillary perfusion was further established (17, 86, 116, 128). In human muscle, it was shown that insulin increased microvascular blood volume (21, 22, 84). Moreover, hyperinsulinemia was shown to enhance skin post-occlusive capillary recruitment and microvascular vasomotion in human skin and muscle (26, 93).

In support of the physiological importance of insulin-induced capillary recruitment, several studies have demonstrated a strong relationship between capillary recruitment and skeletal muscle glucose uptake (22, 29, 86, 93, 115). In addition, specific inhibition of insulin-mediated microvascular effects causes a concomitant 30–40% reduction in glucose disposal (10, 114, 115). This indicates a functional coupling between insulin-induced effects on muscle microvascular perfusion and glucose uptake. This link is underscored by the fact that the vascular actions of insulin are established through stimulation of PI3-kinase-dependent insulin-signaling pathways that bear striking similarities to the metabolic insulin-signaling pathways (63). Both human and rat studies underline this coupling. Obese Zucker rats are characterized by both impaired insulin-induced glucose uptake and impaired capillary recruitment in the basal state and during hyperinsulinemia (117). In human obesity, similar impairments have recently been demonstrated (21, 28, 29, 64).

These findings suggest the involvement of microvascular dysfunction in the development of obesity-related insulin resistance. In terms of cause and effect, there is support for the suggestion that microvascular dysfunction precedes and even predicts the development of insulin resistance and Type 2 diabetes (71, 72, 122). This idea is also supported by studies showing endothelial dysfunction in mildly overweight, normoglycemic subjects with a strong family history of Type 2 diabetes mellitus (13).

	Possible Mechanisms for Obesity-Associated Microvascular Dysfunction

Top Introduction Microcirculation (Definition and... Microvascular Dysfunction in... Microvascular Dysfunction and... Microvascular Dysfunction and... Possible Mechanisms for Obesity... Conclusion References

 
There may be several mechanisms involved in the development of obesity-associated microvascular dysfunction. In the following subsections, we will discuss two main mechanisms.

Intracellular signaling
The metabolic action of insulin to stimulate glucose uptake in skeletal muscle and adipose tissue is mediated through stimulation of PI3-kinase-dependent signaling pathways. These pathways involve the insulin receptor, insulin receptor substrate 1 (IRS-1), PI3-kinase, phosphoinositide-dependent kinase 1 (PDK-1), and protein kinase B (Akt) (63). The vasodilator actions of insulin require highly parallel PI3-kinase-dependent insulin-signaling pathways. Insulin-induced stimulation of Akt directly increases endothelial NO synthase (eNOS) activity, leading to increased NO production (63, 82) (FIGURE 1).

View larger version (65K): [in this window] [in a new window]   FIGURE 1. Mechanisms of insulin-mediated nitric oxide and endothelin 1 production Mechanisms of insulin-mediated nitric oxide (NO) and endothelin 1 (ET-1) production leading to vasodilation and vasoconstriction, respectively. Angiotensin II (AngII), tumor necrosis factor (TNF-), and free fatty acids (FFA) inhibit the PI3-kinase (PI3K) pathway and stimulate the MAPK pathway. IRS-1, insulin receptor substrate 1; PDK-1, phosphoinositide-dependent kinase 1; Akt, protein kinase B; eNOS, endothelial nitric oxide synthase.

Obesity-associated microvascular dysfunction may be caused by cellular defects that influence this balance. First, obesity is associated with an increased production of reactive oxygen species (ROS) (30, 65, 80). ROS limits the bioavailability of NO via reduced NO production and direct inactivation of NO by superoxide (O₂^–) (66). Second, muscle and kidney eNOS expression and activity are diminished in obesity (50, 69, 89, 111, 124), resulting in blunted NO production. Finally, the intracellular insulin signaling transduction pathway is impaired (119). Fatty acid elevation induces phosphorylation of IRS-1 that interferes with insulin-receptor mediated phosphorylation of IRS-1, and in turn results in impaired activation of PI3-kinase (97). As a consequence of these cellular defects, endothelium-derived vasodilation, including insulin-mediated dilation, is blunted in obesity.

In contrast, the signaling pathways for insulin-mediated vasoconstriction seem to be intact or only selectively impaired in obesity. Cardillo et al. (14) demonstrated impaired MAP-kinase pathway activity in obese rats, whereas Jiang et al. (59) showed intact MAP-kinase pathways in the vasculature of obese Zucker rats. However, ERK1/2 activation remains intact in obesity (59). Therefore, insulin-induced vasoconstriction can be demonstrated. In line with this, insulin induced ET-1-dependent vasoconstriction has been shown in skeletal muscle arterioles of obese rats (36).

Thus there is an imbalance between NO and ET-1 production in obesity, wherein the vasoreactivity is shifted from vasodilation toward vasoconstriction. This is further demonstrated in Cardillo’s study in which obese, hypertensive individuals showed insulin-induced vasoconstriction and increased ET-1-dependent vasoconstrictor tone as well as decreased NO-dependent vasodilator tone (14, 48). This endothelial dysfunction may contribute importantly to obesity-associated insulin resistance and obesity-associated hypertension.

Endocrine signaling
Adipokines.
The fact that measures of adiposity and microvascular function are closely linked is strongly suggestive for signaling pathways between adipose tissue and the microcirculation. Adipose tissue functions not merely as a passive storage depot but as a highly active endocrine organ. Adipose tissue, and in particular visceral adipocytes, secrete a variety of bioactive substances called adipokines. In the case of obesity, there is an enhanced production of free fatty acids (FFA) (81), angiotensinogen, leptin, resistin, and several inflammatory cytokines such as tumor necrosis factor (TNF)- and interleukin-6 (IL-6) (52, 99, 121, 127), whereas the production of adiponectin, an anti-inflammatory adipokine, is reduced (7).

FFA and TNF- elevation impair insulin sensitivity and increase blood pressure through mechanisms that are not completely understood but do involve microvascular function (20, 28, 125). In lean rats, acute FFA elevation impairs insulin-mediated capillary recruitment and muscle glucose uptake (20). In addition, human studies also demonstrate endothelial dysfunction in response to FFA exposure. Steinberg et al. (102) and Watanabe et al. (120) demonstrated a reduction in endothelium-dependent vasodilation with intralipid infusion in resistance vessels. In another study, elevation of FFA levels in lean subjects resulted in impaired basal and insulin-induced skin capillary recruitment and endothelium-dependent vasodilation, which was associated with reduced glucose uptake. Conversely, obese women showed improved basal and insulin-mediated skin capillary recruitment and glucose uptake in response to lowering FFA levels (28). In this study, approximately 29% of the effects of FFA elevation or lowering on insulin-induced glucose uptake could be explained by changes in microvascular function, which is consistent with a role for FFA-induced microvascular dysfunction in the development of obesity-associated disorders (28).

The mechanisms by which circulating FFAs impair basal and insulin-mediated effects on microvascular function are not completely understood. First, elevation of FFA blunts insulin-induced PI3-kinase activation in human muscle (31, 97, 119) and in cultured cells (62, 118) (FIGURE 1). Second, FFA elevation induces an increase in ROS production (70). Third, FFA elevation may cause vascular endothelial dysfunction indirectly via increased release of the vasoconstrictor substance ET-1 (81).

Increased production of the proinflammatory cytokine TNF- is associated with obesity-related insulin resistance and hypertension (54, 79, 108). It has been suggested that the vasculature is an important target of TNF- (125, 129). Indeed, in a rat in vivo clamp study, acute administration of TNF- has been shown to inhibit insulin-mediated increases in femoral blood flow and muscle capillary recruitment, leading to a marked decrease in insulin sensitivity. The inhibitory effect of TNF- appeared to be wholly hemodynamic in that insulin-mediated increases in femoral blood flow and capillary recruitment were totally blocked (125). Furthermore, in a human study, weight loss resulted in significant amelioration of endothelial function that closely correlated with a reduction in circulating TNF- (131).

Circulating TNF- may impair insulin-mediated effects on microvascular function by impairing the balance between endothelial-derived vasodilator and vasoconstrictor substances. TNF- downregulates the expression of eNOS (85, 124) and upregulates ET-1 expression in human endothelial cells (73). Furthermore, it may directly activate NAD(P)H oxidase and increase ROS production in the endothelial and vascular smooth muscle cells (30, 58). More importantly, adipose tissue-derived TNF- may suppress insulin-mediated hemodynamic and metabolic effects through inhibition of IRS-1 phosphorylation (53, 121). In addition to these direct effects of TNF-, TNF- may also induce microvascular dysfunction indirectly through stimulation of lipolysis, thereby leading to an increased release of FFAs (FIGURE 1).

Leptin is another adipocyte-derived hormone that rises with increasing percentage of body fat (99, 121), which is likely to be the result of resistance to its appetite-suppressing effects in obesity. Leptin plays an important role in vascular physiology, as leptin signaling in skeletal muscle activates various kinases including PI3-kinase (32). Therefore, decreased leptin signaling leads to impaired insulin-induced microvascular function and, as a consequence, decreased insulin-mediated glucose uptake. Furthermore, increased levels of leptin have been shown to increase ROS production in endothelial cells (99).

Adiponectin is unique amongst the adipokines in that increasing fatness is associated with a lower concentration (7). Adiponectin affects glucose uptake and vascular endothelium via increased phosphorylation of IRS-1 and other molecules in the insulin-signaling cascade (16).

In conclusion, several adipose tissue-derived factors, in particular FFA and TNF-, influence insulin signaling and, thereby, insulin-mediated vasodilation. These endocrine factors therefore provide a potential link between obesity-associated microcirculatory dysfunction and obesity-related hypertension and insulin resistance.

Besides these endocrine factors linking obesity to impaired insulin-induced vasodilation, recently a vasoregulatory role for local deposits of fat has been postulated (126). Obese Zucker rats are characterized by a well circumscribed depot of fat cells around the origin of the nutritive arteriole supplying the cremaster muscle, whereas lean rats are not. Adipokines released by these fat cells may inhibit directly vasodilatory pathways distal in the arteriole and thereby cause loss of blood flow in the nutritive capillary network supplied by this arteriole. In this hypothesis, adipokines released from fat depots have local rather than a systemic vasoregulatory effect, a mechanism that is termed "vasocrine" signaling.

The renin-angiotensin system.
Recent evidence suggests that the renin-angiotensin system (RAS) is another important system involved in microvascular functioning and, consequently, the development of insulin resistance. All the components of the RAS necessary to generate the vasoconstrictor AngII are expressed in human adipose tissue (61, 91). Increased activity of the RAS has been demonstrated in obesity, both systemically and within adipose tissue, and this may relate directly to the mass of adipose tissue (12, 83). Furthermore, a reduction in body weight leads to a reduced RAS activity in plasma and adipose tissue that parallels a fall in blood pressure (33, 110). Given that weight loss reduces systemic RAS activity, adipose tissue RAS components may have paracrine and endocrine functions. This is further supported by the fact that adipose-tissue derived AngII not only binds to receptors on adipocyte plasma membranes but also to presynaptic nerve endings and blood vessels (34).

In healthy subjects, infusion of the vasoconstrictor AngII causes a redirection of blood flow between different vascular beds and within the skeletal muscle vascular bed. This redistribution leads to an increase in total muscle blood flow and capillary recruitment, which as a result increases insulin-induced glucose uptake (18, 38). In contrast, in obesity, the RAS seems to have a detrimental effect on insulin-induced glucose uptake, and activation of the RAS contributes to obesity-associated hypertension (98, 110). Studies have shown increased pressor responses to AngII in rat and men with (visceral) obesity (4, 76, 95). In addition, a rat study demonstrated that AngII-induced hypertension is associated with endothelial dysfunction (45). In addition, chronic AngII administration in rats caused insulin resistance in muscle and adipose tissue (44, 76), whereas blocking the RAS improved insulin sensitivity in muscle of diabetic mice (96). Moreover, several large-scale clinical trials have demonstrated that AngII subtype 1 (AT1) receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEi) decreased the risk for new-onset diabetes mellitus in hypertensive patients by about 25% (2). Whether these protective effects of RAS blockade are attributable to improvements in microvascular function requires further study. Both ACEis and ARBs have been shown to enhance blood flow in peripheral tissues such as skeletal muscle (74, 77). A study in humans showed that a FFA-induced impairment in the endothelial function was completely prevented by a single dose of either an ARB or an ACEi, which suggests that an elevation of FFAs induces endothelial dysfunction through activation of the RAS (120).

Several studies have been conducted to elucidate the mechanisms by which RAS activation impairs endothelial function. First, AngII stimulates phosphorylation of IRS-1 (39, 112), a process that interferes with insulin-dependent activation of PI3-kinase, resulting in inhibited glucose uptake and NO synthase (100). Second, AngII is a well known stimulant of ROS production causing an increased degradation of NO (44, 45, 76, 130). Indeed, recent studies indicated a reduced production of ROS in humans and rats using the ARB valsartan (23, 96). Third, AngII stimulates the production of ET-1 in the endothelium (78, 106) (FIGURE 1). Fourth, AngII is known to have a number of proinflammatory effects, such as the release of inflammatory cytokines (51). For example, incubation of muscle with AngII increased TNF- secretion (108), whereas an ARB or ACE-I decreased skeletal muscle TNF- (96). Finally, it has been proposed that AngII exhibits anti-adipogenic actions, thereby inhibiting adipocyte differentiation and elevating FFA levels. Indeed, blocking the AT1 receptor stimulates adiopogenesis (90).

To summarize, these data suggest an important role for AngII in compromising microvascular function and thus provide another potential link between obesity and insulin resistance and hypertension (FIGURE 2).

View larger version (20K): [in this window] [in a new window]   FIGURE 2. The hypothesised relationships between obesity, microvascular function, hypertension, and impaired insulin-mediated glucose uptake Impaired microvascular function may play a central role in the development of obesity-related disorders.

	Conclusion

Top Introduction Microcirculation (Definition and... Microvascular Dysfunction in... Microvascular Dysfunction and... Microvascular Dysfunction and... Possible Mechanisms for Obesity... Conclusion References

Obesity is associated with several impairments in the microcirculation, including rarefaction and impaired endothelial function. It has been demonstrated that these microvascular dysfunctions not only increase peripheral vascular resistance and blood pressure but also decrease insulin-mediated glucose uptake, and therefore provide a link between obesity and obesity-related disorders. This microvascular dysfunction may be the result of alterations in intracellular and endocrine signaling, in which the RAS may play a prominent role. The detrimental effects of RAS activation on microvascular function in obesity may provide an explanation for the protective effect of RAS blockade for the development of Type 2 diabetes mellitus.

	References

Top Introduction Microcirculation (Definition and... Microvascular Dysfunction in... Microvascular Dysfunction and... Microvascular Dysfunction and... Possible Mechanisms for Obesity... Conclusion References

 

1. Executive. Summary of The Third Report of The National Cholesterol Education Program (N.CEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285: 2486–2497, 2001.[Free Full Text]
2. Abuissa H, Jones PG, Marso SP, O’Keefe Jr JH. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 46: 821–826, 2005.[Abstract/Free Full Text]
3. Agapitov AV, Correia ML, Sinkey CA, Dopp JM, Haynes WG. Impaired skeletal muscle and skin microcirculatory function in human obesity. J Hypertens 20: 1401–1405, 2002.[CrossRef][ISI][Medline]
4. Ames RP, Borkowski AJ, Sicinski AM, Laragh JH. Prolonged infusions of angiotensin II and norepinephrine and blood pressure, electrolyte balance, and aldosterone and cortisol secretion in normal man and in cirrhosis with ascites. J Clin Invest 44: 1171–1186, 1965.[ISI][Medline]
5. Antonios TF, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. Hypertension 34: 655–658, 1999.[Abstract/Free Full Text]
6. Arcaro G, Zamboni M, Rossi L, Turcato E, Covi G, Armellini F, Bosello O, Lechi A. Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity. Int J Obes Relat Metab Disord 23: 936–942, 1999.[CrossRef][ISI][Medline]
7. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257: 79–83, 1999.[CrossRef][ISI][Medline]
8. Baron AD. Cardiovascular actions of insulin in humans. Implications for insulin sensitivity and vascular tone. Baillieres Clin Endocrinol Metab 7: 961–987, 1993.[CrossRef][ISI][Medline]
9. Baron AD. Hemodynamic actions of insulin. Am J Physiol Endocrinol Metab 267: E187–E202, 1994.[Abstract/Free Full Text]
10. Baron AD, Clark MG. Role of blood flow in the regulation of muscle glucose uptake. Annu Rev Nutr 17: 487–499, 1997.[CrossRef][ISI][Medline]
11. Baron AD, Steinberg H, Brechtel G, Johnson A. Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Physiol Endocrinol Metab 266: E248–E253, 1994.[Abstract/Free Full Text]
12. Barton M, Carmona R, Morawietz H, d’Uscio LV, Goettsch W, Hillen H, Haudenschild CC, Krieger JE, Munter K, Lattmann T, Luscher TF, Shaw S. Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin. Hypertension 35: 329–336, 2000.[Abstract/Free Full Text]
13. Caballero AE. Endothelial dysfunction, inflammation, and insulin resistance: a focus on subjects at risk for type 2 diabetes. Curr Diabetes Rep 4: 237–246, 2004.[CrossRef]
14. Cardillo C, Campia U, Iantorno M, Panza JA. Enhanced vascular activity of endogenous endothelin-1 in obese hypertensive patients. Hypertension 43: 36–40, 2004.[Abstract/Free Full Text]
15. Cardillo C, Kilcoyne CM, Nambi SS, Cannon RO, 3rd Quon MJ, Panza JA. Vasodilator response to systemic but not to local hyperinsulinemia in the human forearm. Hypertension 32: 740–745, 1998.[Abstract/Free Full Text]
16. Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care 26: 2442–2450, 2003.[Free Full Text]
17. Clark AD, Barrett EJ, Rattigan S, Wallis MG, Clark MG. Insulin stimulates laser Doppler signal by rat muscle in vivo, consistent with nutritive flow recruitment. Clin Sci (Lond) 100: 283–290, 2001.[CrossRef][ISI][Medline]
18. Clark MG, Colquhoun EQ, Rattigan S, Dora KA, Eldershaw TP, Hall JL, Ye J. Vascular and endocrine control of muscle metabolism. Am J Physiol Endocrinol Metab 268: E797–E812, 1995.[Abstract/Free Full Text]
19. Clark MG, Wallis MG, Barrett EJ, Vincent MA, Richards SM, Clerk LH, Rattigan S. Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab 284: E241–E258, 2003.[Abstract/Free Full Text]
20. Clerk LH, Rattigan S, Clark MG. Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes 51: 1138–1145, 2002.[Abstract/Free Full Text]
21. Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes 55: 1436–1442, 2006.[Abstract/Free Full Text]
22. Coggins M, Lindner J, Rattigan S, Jahn L, Fasy E, Kaul S, Barrett E. Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes 50: 2682–2690, 2001.[Abstract/Free Full Text]
23. Dandona P, Kumar V, Aljada A, Ghanim H, Syed T, Hofmayer D, Mohanty P, Tripathy D, Garg R. Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an anti-inflammatory action. J Clin Endocrinol Metab 88: 4496–4501, 2003.[Abstract/Free Full Text]
24. De Filippis E, Cusi K, Ocampo G, Berria R, Buck S, Consoli A, Mandarino LJ. Exercise-induced improvement in vasodilatory function accompanies increased insulin sensitivity in obesity and type 2 diabetes mellitus. J Clin Endocrinol Metab 91: 4903–4910, 2006.[Abstract/Free Full Text]
25. de Haan CH, van Dielen FM, Houben AJ, de Leeuw PW, Huvers FC, De Mey JG, Wolffenbuttel BH, Schaper NC. Peripheral blood flow and noradrenaline responsiveness: the effect of physiological hyperinsulinemia. Cardiovasc Res 34: 192–198, 1997.[Abstract/Free Full Text]
26. de Jongh RT, Clark AD, RGIJ, Serne EH, de Vries G, Stehouwer CD. Physiological hyperinsulinaemia increases intramuscular microvascular reactive hyperaemia and vasomotion in healthy volunteers. Diabetologia 47: 978–986, 2004.[ISI][Medline]
27. de Jongh RT, Ijzerman RG, Serne EH, Voordouw JJ, Yudkin JS, de Waal HA, Stehouwer CD, van Weissenbruch MM. Visceral and truncal subcutaneous adipose tissue are associated with impaired capillary recruitment in healthy individuals. J Clin Endocrinol Metab 91: 5100–5106, 2006.[Abstract/Free Full Text]
28. de Jongh RT, Serne EH, Ijzerman RG, de Vries G, Stehouwer CD. Free fatty acid levels modulate microvascular function: relevance for obesity-associated insulin resistance, hypertension, and microangiopathy. Diabetes 53: 2873–2882, 2004.[Abstract/Free Full Text]
29. de Jongh RT, Serne EH, RGIJ, de Vries G, Stehouwer CD. Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation 109: 2529–2535, 2004.[Abstract/Free Full Text]
30. De Keulenaer GW, Alexander RW, Ushio-Fukai M, Ishizaka N, Griendling KK. Tumour necrosis factor alpha activates a p22phox-based NADH oxidase in vascular smooth muscle. Biochem J 329: 653–657, 1998.[ISI][Medline]
31. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103: 253–259, 1999.[ISI][Medline]
32. Dyck DJ, Heigenhauser GJ, Bruce CR. The role of adipokines as regulators of skeletal muscle fatty acid metabolism and insulin sensitivity. Acta Physiol (Oxf) 186: 5–16, 2006.[CrossRef]
33. Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM. Weight loss and the renin-angiotensin-aldosterone system. Hypertension 45: 356–362, 2005.[Abstract/Free Full Text]
34. Engeli S, Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G, Teboul M, Massiera F, Sharma AM. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? Int J Biochem Cell Biol 35: 807–825, 2003.[CrossRef][ISI][Medline]
35. Eringa EC, Stehouwer CD, van Nieuw Amerongen GP, Ouwehand L, Westerhof N, Sipkema P. Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium. Am J Physiol Heart Circ Physiol 287: H2043–H2048, 2004.[Abstract/Free Full Text]
36. Eringa EC, Stehouwer CD, Walburg K, Clark AD, van Nieuw Amerongen GP, Westerhof N, Sipkema P. Physiological concentrations of insulin induce endothelin-dependent vasoconstriction of skeletal muscle resistance arteries in the presence of tumor necrosis factor-alpha dependence on c-Jun N-terminal kinase. Arterioscler Thromb Vasc Biol 26: 274–280, 2006.[Abstract/Free Full Text]
37. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 288: 1723–1727, 2002.[Abstract/Free Full Text]
38. Fliser D, Dikow R, Demukaj S, Ritz E. Opposing effects of angiotensin II on muscle and renal blood flow under euglycemic conditions. J Am Soc Nephrol 11: 2001–2006, 2000.[Abstract/Free Full Text]
39. Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP. Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. J Clin Invest 100: 2158–2169, 1997.[ISI][Medline]
40. Frisbee JC. Hypertension-independent microvascular rarefaction in the obese Zucker rat model of the metabolic syndrome. Microcirculation 12: 383–392, 2005.[CrossRef][ISI][Medline]
41. Frisbee JC. Impaired skeletal muscle perfusion in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 285: R1124–R1134, 2003.[Abstract/Free Full Text]
42. Frisbee JC. Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 289: R307–R316, 2005.[Abstract/Free Full Text]
43. Frisbee JC, Samora JB, Peterson J, Bryner R. Exercise training blunts microvascular rarefaction in the metabolic syndrome. Am J Physiol Heart Circ Physiol 291: H2483–H2492, 2006.[Abstract/Free Full Text]
44. Fujita T. Spotlight on renin. The renin system, salt-sensitivity and metabolic syndrome. J Renin Angiotensin Aldosterone Syst 7: 181–183, 2006.[CrossRef][ISI][Medline]
45. Fujita T. Symposium on the etiology of hypertension: summarizing studies in 20th century. 5 Renin-angiotensin system and hypertension. Intern Med 40: 156–158, 2001.[ISI][Medline]
46. Gavin TP, Stallings HW 3rd, Zwetsloot KA, Westerkamp LM, Ryan NA, Moore RA, Pofahl WE, Hickner RC. Lower capillary density but no difference in VEGF expression in obese vs. lean young skeletal muscle in humans. J Appl Physiol 98: 315–321, 2005.[Abstract/Free Full Text]
47. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109: 433–438, 2004.[Free Full Text]
48. Gudbjornsdottir S, Elam M, Sellgren J, Anderson EA. Insulin increases forearm vascular resistance in obese, insulin-resistant hypertensives. J Hypertens 14: 91–97, 1996.[ISI][Medline]
49. Han TS, Feskens EJ, Lean ME, Seidell JC. Associations of body composition with type 2 diabetes mellitus. Diabet Med 15: 129–135, 1998.[CrossRef][ISI][Medline]
50. Hickner RC, Kemeny G, Stallings HW, Manning SM, McIver KL. Relationship between body composition and skeletal muscle eNOS. Int J Obes 30: 308–312, 2006.[CrossRef][ISI][Medline]
51. Horiuchi M, Mogi M, Iwai M. Signaling crosstalk angiotensin II receptor subtypes and insulin. Endocr J 53: 1–5, 2006.[CrossRef][ISI][Medline]
52. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95: 2409–2415, 1995.[ISI][Medline]
53. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271: 665–668, 1996.[Abstract]
54. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259: 87–91, 1993.[Abstract/Free Full Text]
55. Houben AJ, Canoy MC, Paling HA, Derhaag PJ, de Leeuw PW. Quantitative analysis of retinal vascular changes in essential and renovascular hypertension. J Hypertens 13: 1729–1733, 1995.[ISI][Medline]
56. Houben AJ, Willemsen RT, van de Ven H, de Leeuw PW. Microvascular adaptation to changes in dietary sodium is disturbed in patients with essential hypertension. J Hypertens 23: 127–132, 2005.[CrossRef][ISI][Medline]
57. Ikram MK, Witteman JC, Vingerling JR, Breteler MM, Hofman A, de Jong PT. Retinal vessel diameters and risk of hypertension: the Rotterdam Study. Hypertension 47: 189–194, 2006.[Abstract/Free Full Text]
58. Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49: 1939–1945, 2000.[Abstract]
59. Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 104: 447–457, 1999.[ISI][Medline]
60. Johnson PC. Active and passive determinants of capillary density: a historical perspective. Int J Microcirc Clin Exp 15: 218–222, 1995.[ISI][Medline]
61. Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, Carlsson LM. Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab 83: 3925–3929, 1998.[Abstract/Free Full Text]
62. Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol 25: 989–994, 2005.[Abstract/Free Full Text]
63. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 113: 1888–1904, 2006.[Abstract/Free Full Text]
64. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest 85: 1844–1852, 1990.[ISI][Medline]
65. Laight DW, Kengatharan KM, Gopaul NK, Anggard EE, Carrier MJ. Investigation of oxidant stress and vasodepression to glyceryl trinitrate in the obese Zucker rat in vivo. Br J Pharmacol 125: 895–901, 1998.[CrossRef][ISI][Medline]
66. Landmesser U, Harrison DG, Drexler H. Oxidant stress-a major cause of reduced endothelial nitric oxide availability in cardiovascular disease. Eur J Clin Pharmacol 62, Suppl 1: 13–19, 2006.[CrossRef]
67. le Noble JL, Tangelder GJ, Slaaf DW, van Essen H, Reneman RS, Struyker-Boudier HA. A functional morphometric study of the cremaster muscle microcirculation in young spontaneously hypertensive rats. J Hypertens 8: 741–748, 1990.[CrossRef][ISI][Medline]
68. Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation 104: 735–740, 2001.[Free Full Text]
69. Li Z, Rodriguez-Iturbe B, Ni Z, Shahkarami A, Sepassi L, Vaziri ND. Effect of hereditary obesity on renal expressions of NO synthase, caveolin-1, AKt, guanylate cyclase, and calmodulin. Kidney Int 68: 2766–2772, 2005.[CrossRef][ISI][Medline]
70. Lu G, Greene EL, Nagai T, Egan BM. Reactive oxygen species are critical in the oleic acid-mediated mitogenic signaling pathway in vascular smooth muscle cells. Hypertension 32: 1003–1010, 1998.[Abstract/Free Full Text]
71. Meigs JB, Hu FB, Rifai N, Manson JE. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA 291: 1978–1986, 2004.[Abstract/Free Full Text]
72. Meigs JB, O’Donnell CJ, Tofler GH, Benjamin EJ, Fox CS, Lipinska I, Nathan DM, Sullivan LM, D’Agostino RB, Wilson PW. Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study. Diabetes 55: 530–537, 2006.[Abstract/Free Full Text]
73. Mohamed F, Monge JC, Gordon A, Cernacek P, Blais D, Stewart DJ. Lack of role for nitric oxide (NO) in the selective destabilization of endothelial NO synthase mRNA by tumor necrosis factor-alpha. Arterioscler Thromb Vasc Biol 15: 52–57, 1995.[Abstract/Free Full Text]
74. Morel Y, Gadient A, Keller U, Vadas L, Golay A. Insulin sensitivity in obese hypertensive dyslipidemic patients treated with enalapril or atenolol. J Cardiovasc Pharmacol 26: 306–311, 1995.[ISI][Medline]
75. Noon JP, Walker BR, Webb DJ, Shore AC, Holton DW, Edwards HV, Watt GC. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 99: 1873–1879, 1997.[ISI][Medline]
76. Ogihara T, Asano T, Ando K, Chiba Y, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiro M, Katagiri H, Fukushima Y, Kikuchi M, Noguchi N, Aburatani H, Komuro I, Fujita T. Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling. Hypertension 40: 872–879, 2002.[Abstract/Free Full Text]
77. Olsen MH, Fossum E, Hoieggen A, Wachtell K, Hjerkinn E, Nesbitt SD, Andersen UB, Phillips RA, Gaboury CL, Ibsen H, Kjeldsen SE, Julius S. Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy. J Hypertens 23: 891–898, 2005.[ISI][Medline]
78. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 86: 747–803, 2006.[Abstract/Free Full Text]
79. Pausova Z, Deslauriers B, Gaudet D, Tremblay J, Kotchen TA, Larochelle P, Cowley AW, Hamet P. Role of tumor necrosis factor-alpha gene locus in obesity and obesity-associated hypertension in French Canadians. Hypertension 36: 14–19, 2000.[Abstract/Free Full Text]
80. Perticone F, Ceravolo R, Candigliota M, Ventura G, Iacopino S, Sinopoli F, Mattioli PL. Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C. Diabetes 50: 159–165, 2001.[Abstract/Free Full Text]
81. Piatti PM, Monti LD, Conti M, Baruffaldi L, Galli L, Phan CV, Guazzini B, Pontiroli AE, Pozza G. Hypertriglyceridemia and hyperinsulinemia are potent inducers of endothelin-1 release in humans. Diabetes 45: 316–321, 1996.[Abstract]
82. Potenza MA, Marasciulo FL, Chieppa DM, Brigiani GS, Formoso G, Quon MJ, Montagnani M. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol Heart Circ Physiol 289: H813–H822, 2005.[Abstract/Free Full Text]
83. Rahmouni K, Mark AL, Haynes WG, Sigmund CD. Adipose depot-specific modulation of angiotensinogen gene expression in diet-induced obesity. Am J Physiol Endocrinol Metab 286: E891–E895, 2004.[Abstract/Free Full Text]
84. Raitakari M, Knuuti MJ, Ruotsalainen U, Laine H, Makea P, Teras M, Sipila H, Niskanen T, Raitakari OT, Iida H, et al. Insulin increases blood volume in human skeletal muscle: studies using [¹⁵O]CO and positron emission tomography. Am J Physiol Endocrinol Metab 269: E1000–E1005, 1995.[Abstract/Free Full Text]
85. Rask-Madsen C, King GL. Mechanisms of disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab 3: 46–56, 2007.[CrossRef][ISI][Medline]
86. Rattigan S, Clark MG, Barrett EJ. Acute vasoconstriction-induced insulin resistance in rat muscle in vivo. Diabetes 48: 564–569, 1999.[Abstract]
87. Rattigan S, Clark MG, Barrett EJ. Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment. Diabetes 46: 1381–1388, 1997.[Abstract]
88. Reaven Banting lecture 1988 GM. Role of insulin resistance in human disease. Diabetes 37: 1595–1607, 1988.[Abstract]
89. Roberts CK, Barnard RJ, Sindhu RK, Jurczak M, Ehdaie A, Vaziri ND. A high-fat, refined-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant imbalance and depresses NOS protein expression. J Appl Physiol 98: 203–210, 2005.[Abstract/Free Full Text]
90. Schling P, Loffler G. Effects of angiotensin II on adipose conversion and expression of genes of the renin-angiotensin system in human preadipocytes. Horm Metab Res 33: 189–195, 2001.[CrossRef][ISI][Medline]
91. Schling P, Mallow H, Trindl A, Loffler G. Evidence for a local renin angiotensin system in primary cultured human preadipocytes. Int J Obes Relat Metab Disord 23: 336–341, 1999.[CrossRef][ISI][Medline]
92. Serne EH, Gans RO, ter Maaten JC, ter Wee PM, Donker AJ, Stehouwer CD. Capillary recruitment is impaired in essential hypertension and relates to insulin’s metabolic and vascular actions. Cardiovasc Res 49: 161–168, 2001.[CrossRef][ISI][Medline]
93. Serne EH, RGIJ, Gans RO, Nijveldt R, De Vries G, Evertz R, Donker AJ, Stehouwer CD. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes 51: 1515–1522, 2002.[Abstract/Free Full Text]
94. Serne EH, Stehouwer CD, ter Maaten JC, ter Wee PM, Rauwerda JA, Donker AJ, Gans RO. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects. Circulation 99: 896–902, 1999.[Abstract/Free Full Text]
95. Shinozaki K, Ayajiki K, Nishio Y, Sugaya T, Kashiwagi A, Okamura T. Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension 43: 255–262, 2004.[Abstract/Free Full Text]
96. Shiuchi T, Iwai M, Li HS, Wu L, Min LJ, Li JM, Okumura M, Cui TX, Horiuchi M. Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. Hypertension 43: 1003–1010, 2004.[Abstract/Free Full Text]
97. Shulman GI. Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology Bethesda 19: 183–190, 2004.[CrossRef][Medline]
98. Simon G, Abraham G, Cserep G. Pressor and sub-pressor angiotensin II administration. Two experimental models of hypertension. Am J Hypertens 8: 645–650, 1995.[CrossRef][ISI][Medline]
99. Singhal A. Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD. Proc Nutr Soc 64: 15–22, 2005.[CrossRef][ISI][Medline]
100. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 37: 1053–1059, 2001.[Abstract/Free Full Text]
101. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 97: 2601–2610, 1996.[ISI][Medline]
102. Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B, Baron AD. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 100: 1230–1239, 1997.[ISI][Medline]
103. Stepp DW. Impact of obesity and insulin resistance on vasomotor tone: nitric oxide and beyond. Clin Exp Pharmacol Physiol 33: 407–414, 2006.[CrossRef][ISI][Medline]
104. Struijker Boudier HA, le Noble JL, Messing MW, Huijberts MS, le Noble FA, van Essen H. The microcirculation and hypertension. J Hypertens Suppl 10: S147–S156, 1992.[CrossRef][Medline]
105. Tack CJ, Lutterman JA, Vervoort G, Thien T, Smits P. Activation of the sodium-potassium pump contributes to insulin-induced vasodilation in humans. Hypertension 28: 426–432, 1996.[Abstract/Free Full Text]
106. Taddei S, Grassi G. Angiotensin II as the link between nitric oxide and neuroadrenergic function. J Hypertens 23: 935–937, 2005.[ISI][Medline]