Obesity is associated with increased cardiovascular morbidity and mortality in part due to vascular abnormalities such as endothelial dysfunction and arterial stiffening. The hypertension and other health complications that arise from these vascular defects increase the risk of heart diseases and stroke. Prooxidant and proinflammatory signaling pathways as well as adipocyte-derived factors have emerged as critical mediators of obesity-associated vascular abnormalities. Designing treatments aimed specifically at improving the vascular dysfunction caused by obesity may provide an effective therapeutic approach to prevent the cardiovascular sequelae associated with excessive adiposity. In this review, we discuss the recent evidence supporting the role of oxidative stress and cytokines and inflammatory signals within the vasculature as well as the impact of the surrounding perivascular adipose tissue (PVAT) on the regulation of vascular function and arterial stiffening in obesity. In particular, we focus on the highly plastic nature of the vasculature in response to altered oxidant and inflammatory signaling and highlight how weight management can be an effective therapeutic approach to reduce the oxidative stress and inflammatory signaling and improve vascular function.

Introduction

With current estimates of excess adiposity (overweight and obese) affecting nearly 30% of the population worldwide this global epidemic has become a serious public health issue [1]. Obesity is commonly associated with several medical complications including Type 2 diabetes and insulin resistance, as well as an assortment of cardiovascular diseases such as peripheral and coronary artery disease, stroke, and heart failure. The increased risk of cardiovascular morbidity and mortality associated with obesity is due to a myriad of factors such as autonomic dysfunction, dysregulated adipose tissue signaling, and vascular defects in the periphery such as endothelial dysfunction and arterial stiffening all of which promote the development of hypertension, a major risk factor for the cardiovascular diseases.

Long-term epidemiological studies such as The Framingham Heart Study have clearly established a link between the rise in adiposity and blood pressure elevation in humans [2,3]. Indeed, increased body weight confers a 3-fold higher risk for the development of hypertension compared to individuals with normal body weight [3]. Current estimates suggest the prevalence of hypertension in obese humans is over 50% [4] and recently the Dallas Heart Study has demonstrated that higher body mass index (BMI) in humans is significantly associated with hypertension and this incidence specifically correlates with visceral or abdominal adiposity and not total or subcutaneous adipose tissue [5]. Taken together, these studies highlight the need for mechanistic insights into the links between obesity and hypertension.

Vascular dysfunction is well documented as an important process in driving the pathologies associated with obesity and hypertension [6,7]. Human and animal models of obesity have demonstrated altered vascular contractility and decreased dilator function that can promote hypertension [8,9]. The mechanisms causing this vascular dysfunction involve the combinatorial effect of oxidative stress and inflammatory signaling that are widely recognized as major players in the pathogenesis of cardiovascular diseases and hypertension [10]. In this review, we will briefly summarize the current knowledge and highlight recent advances in our understanding of the vascular consequences of obesity and the resulting hypertension focusing particularly on the role of oxidative stress, inflammation, and cytokines as critical mediators of the vascular dysfunction associated with the increased adiposity and as potential targets for therapeutic intervention and medical management.

Development of vascular dysfunction in obesity

Obesity has long been known to be associated with vascular abnormalities including endothelial dysfunction, enhanced contractile responses to vasoconstrictors, and structural remodeling of the vascular wall [1114], all of which contribute and predict the development of cardiovascular diseases. Both clinical and animal studies have pointed to alterations in a variety of signaling pathways in obesity that promote vascular abnormalities such as excessive reactive oxygen species (ROS) production, the renin–angiotensin–aldosterone system (RAAS), proinflammatory/immune signaling, and reduced nitric oxide (NO) bioavailability and activity [7,1518]. Of particular interest is the timing that the vascular changes manifest themselves as obesity develops, which is an important factor to consider. In animal models, the time course for the development of endothelial dysfunction largely depends on the composition of the high fat diet, the initiation of the diet, and the vascular bed. In the large conduit arteries such as the aorta [12] and carotid [19], a moderate high-fat diet 45% kcal requires ∼8–9 months of continuous feeding to induce endothelial dysfunction. However, in a more resistance vasculature of the cerebral circulation, 12 weeks are sufficient to induce endothelial dysfunction [19]. It is currently unclear as to why this differential timing in the manifestation of the endothelial dysfunction upon high-fat feeding, but may relate to dissimilar processes that underlie reactivity of large versus small arteries or different triggering thresholds for the signaling pathways to shift the balance to vascular dysfunction.

It is important to note that obesity does not always result in vascular endothelial dysfunction. For instance, mouse models of Bardet Biedl syndrome (BBS), bearing global knockout of certain BBS proteins results in obesity and an increase in arterial pressure, contrasting effects on vascular relaxation have been noted depending on which Bbs gene is deleted. Global knockout of Bbs6 gene in mice results in obesity associated with no change in endothelial function while Bbs2 knockout mice that were also obese exhibited enhanced acetylcholine-mediated aortic vasorelaxation [20]. These findings indicate that presence of BBS proteins is required for the vascular abnormalities to manifest in obesity. The mechanisms underlying the disparity in vascular function between the two BBS mouse models seem to relate to changes in the expression of the NO-producing enzymes and NAPDH oxidase that determines ROS production. Indeed, the expression of eNOS and iNOS were up-regulated in the aorta of Bbs2 null mice, but not Bbs6 knockout mice whereas the aortic expression of NAPDH oxidase subunits p22(phox) and p47(phox) was decreased in Bbs2 knockout mice but increased in Bbs6 null mice [20,21]. It remains to be determined if blockade of NO, ROS, or inflammatory signaling in the Bbs2 and Bbs6 null mouse models will interfere with the endothelial-mediated relaxation.

Furthermore, a study by Beyer and colleagues using Dahl salt sensitive rats, which possess chronically lower RAAS, found these animals to be resistant to the vascular effects evoked by high-fat diet feeding in spite of significant weight gain [22], possibly due to increases in superoxide dismutase expression in cerebral arteries reducing the prooxidant vascular environment associated with obesity. The mechanism for this resistance to high-fat diet-induced endothelial dysfunction remains unclear but may relate to the suppressed RAAS [22] as reduction in RAAS components lead to similar protective effects against obesity [23,24].

Vascular insulin resistance in obesity

Insulin resistance is commonly associated with obesity whereby circulating insulin has a decreased ability upon binding to its receptor to activate downstream intracellular signaling. In the vasculature, insulin receptors are expressed in both endothelial and vascular smooth muscle cells with primary signaling effects on NO vasorelaxing signaling pathway as well as regulation of cellular proliferation via the mitogen-activated protein kinase (MAPK) signaling pathway [25,26]. In endothelial cells, insulin activates the production of NO via the phosphaditylinositol-3 kinase (PI3K) pathway through the phosphorylation of eNOS at its activating site (Ser1177) [26]. In smooth muscle cells, insulin works primarily through the MAPK pathway regulating cellular processes involved in migration and proliferation. Clearly, insulin levels can play a major role in the regulation of vascular homeostasis.

Increased circulating insulin levels are commonly associated with obesity where increased ROS and inflammatory signaling in the vasculature contributes to the compromised bioavailability of NO and impaired vascular responses [7,27]. However, the role of insulin resistance in obesity particularly in the concept of selective insulin resistance within the vasculature is controversial. In obesity, increased insulin seems to be shuttled toward the MAPK signaling pathway resulting in endothelial cell proliferation, which is commonly associated with vascular diseases [26,28]. Interestingly, hyperinsulinemia in cultured vascular smooth muscle cells can promote the inflammatory effects of fatty acids [29] as well as increased ROS production [30]. This reduction in the insulin-stimulated PI3K–eNOS signaling pathway in obesity reduces the vasculoprotective effects of NO as well as its anti-inflammatory actions [31].

A study by Symons and colleagues [32] demonstrated that mice lacking insulin receptors in the vasculature displayed no change in vascular eNOS expression and both vascular function and blood pressure remain normal despite the hyperinsulinemia. However, when these conditional null mice were challenged with high-fat diet, activation of eNOS phosphorylation was completely abolished and deficits in endothelial function and increased blood pressure manifest suggesting that factors other than the insulin receptors may be involved in the regulation of vascular insulin resistance. It is important to note that rescue of endothelial eNOS activity in obesity has been demonstrated to suppress NF-kB signaling resulting in the reversal of endothelial insulin resistance [33]. The mechanism underlying this effect seems to involve reduction in plasma levels of oxidative stress markers such as T-BARS and 8-isoprostane levels as well as reductions in oxidative stress within infiltrating macrophages through reductions in iNOS expression [33].

Oxidative stress and inflammation in obesity-related endothelial dysfunction

Obesity is commonly associated with a chronic low grade inflammatory state [34] as well as elevated vascular oxidative stress. This is characterized by increases in localized cytokine, ROS production and secretion, and activation of immune cells. Research over the past decade has enhanced our understanding as how these inflammatory and oxidant markers interact with other signaling pathways to mediate the vascular changes evoked by obesity. We will highlight some recent advances in our understanding of the interactions between oxidant and inflammatory signaling and signaling derived from the immune system, leptin secretion, and signaling arising from the perivascular adipose tissue (PVAT) in obesity (Figure 1).

Overview of the biological processes that links obesity, oxidant and inflammatory signaling, and vascular dysfunction leading to hypertension.

Figure 1
Overview of the biological processes that links obesity, oxidant and inflammatory signaling, and vascular dysfunction leading to hypertension.

Fat mass accumulation in obesity leads to activation of local oxidative and inflammatory markers in conjunction with activation of immune and PVAT signals. Prooxidant and inflammatory factors contribute directly to vascular dysfunction through effects on the endothelium and NO bioavailability (endothelial dysfunction) and the vascular wall (arterial stiffening) both of which promote hypertension. Weight loss and body weight management reduces (−) prooxidant, proinflammatory, and immune signaling and enhances NO bioavailability alleviating the vascular abnormalities and hypertension; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein 1; TNFα, tumor necrosis factor α.

Figure 1
Overview of the biological processes that links obesity, oxidant and inflammatory signaling, and vascular dysfunction leading to hypertension.

Fat mass accumulation in obesity leads to activation of local oxidative and inflammatory markers in conjunction with activation of immune and PVAT signals. Prooxidant and inflammatory factors contribute directly to vascular dysfunction through effects on the endothelium and NO bioavailability (endothelial dysfunction) and the vascular wall (arterial stiffening) both of which promote hypertension. Weight loss and body weight management reduces (−) prooxidant, proinflammatory, and immune signaling and enhances NO bioavailability alleviating the vascular abnormalities and hypertension; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein 1; TNFα, tumor necrosis factor α.

Immune signaling

Numerous immune signaling components have been implicated in the vascular dysfunction caused by obesity and hypertension through their interaction with inflammatory signaling pathways [3538]. One such immune signaling component relate to monocyte signaling (Figure 2). Monocytes express various receptors that allow these immune cells to interact with the vasculature contributing to homeostasis of the endothelium [39]. However, when the vasculature is challenged via increased inflammation, monocytes are activated potentiating further the inflammatory response promoting alterations in vascular endothelial function [40]. In a study by Wenzel and colleagues, removal of circulating monocytes in the mouse induced by diphtheria toxin was found to prevent the normal hypertensive response to angiotensin II infusion while reintroduction of these monocytes restored the hypertensive response [41]. In addition, eliminating monocytes enhanced the vasorelaxation responses of the aorta to acetylcholine-mediated dilation pointing to a primary effect of monocytes on the vascular endothelium [41].

Vascular monocytes signaling in obesity.

Figure 2
Vascular monocytes signaling in obesity.

Under normal physiological settings (steady state), circulating monocytes contribute to vascular endothelial homeostasis. In obesity, increased expression of MCP-1 recruits activated monocytes to the endothelium to activate signal cascades within the endothelium increasing expression of proinflammatory cytokines such as TNFα, IL-6, and free fatty acids (FFA).

Figure 2
Vascular monocytes signaling in obesity.

Under normal physiological settings (steady state), circulating monocytes contribute to vascular endothelial homeostasis. In obesity, increased expression of MCP-1 recruits activated monocytes to the endothelium to activate signal cascades within the endothelium increasing expression of proinflammatory cytokines such as TNFα, IL-6, and free fatty acids (FFA).

Notably, obese women were found to have increased levels of activated monocytes compared with lean counterparts [42]. Circulating mononuclear cells isolated from obese humans have been demonstrated to exist in a proinflammatory, prooxidant state with increases in TNFα, IL-6, C-reactive protein, and FFA [43]. In addition, a study of monocytes isolated from obese patients identified three distinct subpopulations of activated monocytes that were associated with altered gene expression of several proinflammatory cytokines including IL-1β and TNFα [44] demonstrating the connection between altered immune signaling and activated inflammatory responses in obesity.

Monocytes are recruited to the endothelium by MCP-1, which is a chemokine secreted from both PVAT and the vascular endothelium. MCP-1 has been demonstrated to enhance leukocyte infiltration into vascular cells promoting further inflammatory responses [45]. Interestingly, in the Framingham Heart Study, urinary isoprostane levels correlated with circulating levels of MCP-1 and level of visceral adipose tissue [46]. Indeed, MCP-1 levels are elevated in the visceral adipose tissue isolated from obese individuals [47], in adipose tissue of obese mice [48] as well as the vasculature of obese Zucker rats [49]. Moreover, knocking out MCP-1 prevents the development of obesity evoked by high-fat diet in mice [48]. However, vascular function was not measured in this study. Thus, it remains to be determined if vascular function is preserved in absence of MCP-1.

Leptin signaling

Leptin is a 16 kDa cytokine [50] that circulates at elevated levels, in proportion to adipose tissue mass, in obese human and animal models. Hyperleptinemia has been implicated in a variety of cardiovascular risks such as atherosclerosis, hypertension, and cardiac hypertrophy [5153] and is an independent predictor of cardiovascular mortality and morbidity [54]. Leptin’s action in the brain to regulate energy homeostasis is well established, regulating the balance between energy intake, expenditure, and storage. Leptin receptors are highly expressed throughout the brain and play a critical role in the regulation of the activity of the sympathetic nervous system, thus affecting the cardiovascular system [55]. Interestingly, leptin receptors are also expressed in several peripheral tissues including the endothelium and smooth muscle of the vasculature [56]. Acute leptin application results in dilation of rat [57] and canine [58] mesenteric arteries as well as the large conduit of the rabbit aorta [59] through a mechanism involving NO. However, the role of leptin signaling in the regulation of vascular function as well as in pathological conditions such as obesity where leptin levels are elevated remains unclear.

In cultured vascular endothelial cells, acute treatment with leptin results in increased NO signaling through a process implicating signal transducer and activator of transcription 3 and phosphatidylinositol 3-kinase/AKT signaling pathway [60] indicating direct effects of leptin in endothelial cells. However, chronic exposure (72 h) of endothelial cells to leptin yielded an opposite effect decreasing NO production through a mechanism involving suppressor of cytokine signaling 3 (SOCS3) signaling indicating detrimental effects on vascular cells of prolonged exposure to leptin [61]. In aortic endothelial cells, leptin was shown to induce ROS production and increases monocyte MCP-1 expression via protein kinase A signaling and fatty acid oxidation pointing to leptin as both a prooxidant and proinflammatory activator in endothelial cells [62].

In animal models of increased circulating leptin such as high fat diet-induced obesity [63], prolonged elevation in levels of leptin results in endothelial-mediated reductions in vasorelaxation responses to acetylcholine as well as contractility changes to calcium mobilization within the smooth muscle [12]. Recently, a study by Ryan and colleagues demonstrated that incubation of mouse carotid arterial rings with high concentrations of leptin mimicking the hyperleptinemia associated with morbid obesity resulted in reduced acetylcholine-mediated relaxation without any changes in the relaxation responses evoked by sodium nitroprusside (SNP) indicating that chronic hyperleptinemia evoke endothelial but not smooth muscle dysfunction [64]. This finding was extended to the coronary microcirculation as elevating leptin levels caused endothelial dysfunction in this resistance vascular bed [65].

Interestingly, injection of C57BL6/J mice with recombinant leptin once a day for a period of 1 week resulted in severe endothelial-mediated relaxation of mesenteric resistance arterioles with no changes in SNP-induced relaxation [66]. These findings seem to point to the endothelial cells as the main site of leptin action in the vasculature. It should be noted, however, that vascular smooth-specific deletion of the leptin receptor attenuated leptin-mediated acetylcholine-induced relaxation raising the possible contribution of leptin action in smooth muscle cells to the regulation of endothelial function [64].

Prooxidant signaling appears to mediate the endothelial action of leptin as indicated by the blunting effects of superoxide scavenger Tempol on the endothelial function impairment induced by leptin treatment [66]. However, as with the acute in vitro cellular experiments, timing of the increase in circulating leptin levels is important. Acute infusion of leptin into leptin-deficient ob/ob mice enhances the vasodilation induced by acetylcholine, measured ex vivo [60], indicating a beneficial effect of leptin on vascular function whereas chronic leptin infusion in rats and mice increases arterial pressure [67,68]. In a randomized clinical trial, weight loss in obese subjects reduced plasma leptin concentrations significantly reflecting a decrease in adiposity [69]. The reduction in fat mass and circulating leptin levels were positively associated with the improvement in forearm blood flow during intrabrachial artery infusion of acetylcholine, further supporting the role of chronic hyperleptinemia as a key driver of endothelial dysfunction in obesity [69].

PVAT-derived factors

PVAT is a layer of fat tissue encasing the blood vessels that acts as a dynamic endocrine organ exerting differential effects on vascular reactivity depending on level of adiposity (Figure 3). When adiposity is normal, PVAT signaling is primarily anticontractile on the surrounding vasculature working through a mechanism that involves enhancement of NO bioavailability and activity within the vascular endothelium [70]. This anticontractile effect is lost in obese human and animal models of obesity [71] that likely contributes to the vascular dysfunction as well as the hypertension associated with excess of adiposity. During early stages of obesity, NO overproduction occurs within the PVAT perhaps aimed at maintaining vascular function [72]. However, as the pathology of obesity progresses there is a reduction in endothelial eNOS expression in vascular tissues and concomitant increase in TNFα expression in the PVAT leading to an increase in both oxidative stress and inflammation/chemokine production within the adipose tissue. Interestingly, decreased endothelial-mediated relaxation of the aorta associated with obesity was attenuated by the removal of the PVAT whereas obesity-related increase in vascular contractility was not affected [73]. Moreover, PVAT isolated from high-fat diet fed rats impairs acetylcholine-induced dilation of aortic and mesenteric arterial rings of lean rats demonstrating that in obesity PVAT releases factors that interfere with the endothelium-mediated relaxation [73].

PVAT signaling in obesity.

Figure 3
PVAT signaling in obesity.

PVAT mass and signaling activity are increased in response to obesity with increased expression of inflammatory cytokines (IL-6, TNFα), chemokine/hormones (chemerin, leptin), ROS signaling, and decreases in adiponectin secretion and NO signaling. This PVAT signaling milieu affects both endothelial and smooth muscle cells in the vasculature. In endothelial cells, PVAT signaling decreases NO bioavailability along with concomitant increases in pro-ROS and inflammatory signaling. In smooth muscle cells, PVAT signaling increases contractility, cellular proliferation, and migration as well as contributes to obesity-induced arterial stiffening.

Figure 3
PVAT signaling in obesity.

PVAT mass and signaling activity are increased in response to obesity with increased expression of inflammatory cytokines (IL-6, TNFα), chemokine/hormones (chemerin, leptin), ROS signaling, and decreases in adiponectin secretion and NO signaling. This PVAT signaling milieu affects both endothelial and smooth muscle cells in the vasculature. In endothelial cells, PVAT signaling decreases NO bioavailability along with concomitant increases in pro-ROS and inflammatory signaling. In smooth muscle cells, PVAT signaling increases contractility, cellular proliferation, and migration as well as contributes to obesity-induced arterial stiffening.

The identity of the PVAT-derived factors that interfere with endothelial reactivity is not clear, but several mechanisms have been proposed including aldosterone and leptin [9]. The ability of PVAT to affect vascular function is also influenced by circulating factors. For instance, circulating FFA, which are elevated in obesity [74], were found to interfere with the anticontractile properties of PVAT. Notably, this occurs through an endothelium-dependent rather than an endothelium-independent mechanism and results in an increase in contractility of aortic rings through a process that involves NF-κB [75,76]. Thus, it is clear that altered PVAT signaling in obesity contributes to the vascular dysfunction through processes that involve both prooxidant and proinflammatory signaling pathways.

The precise inflammatory mechanisms by which PVAT signaling affects vascular function in obesity are emerging. For instance, addition of IL-6 or TNFα to PVAT of blood vessels of healthy subjects attenuated the dilatory response recapitulating the defect observed in obesity [77]. These vascular changes were rescued by application of free radical scavengers or anti-cytokine antibodies. Moreover, stimulation of hypoxia-mediated increase in inflammation interfered with the anticontractile capacity of PVAT through a process that implicates catalase, superoxide dismutase, and cytokines [77].

Blockade of adiponectin type 1 receptor or eNOS inhibited the vasodilator effect of healthy PVAT implicating adiponectin as a potential link between PVAT and endothelial function by modulating NO bioavailability [77]. Studies in ob/ob mice PVAT have also implicated the paracrine effect of leptin as an important mediator of perivascular inflammation [78]. Furthermore, the anticontractile effect of perivascular leptin is reduced in hypertension possibly through inflammatory factors that reduce NO bioavailability [79].

The chemokine chemerin has recently emerged as a potential link between PVAT signaling, inflammation, and vascular endothelial function in obesity and hypertension. In a meta-analysis study, Li et al. [80] demonstrated that circulating chemerin levels are positively correlated to both BMI and total body fat percentage in humans. Interestingly, in humans the increases in plasma levels of chemerin were found to be associated with decreases in vascular endothelial function and increases in arterial stiffening [81] indicating possible vasoactive effects of chemerin. Indeed, a study by Watts and colleagues demonstrated that chemerin acts as a vasoconstrictor in rodent arteries and interestingly increased chemerin-induced contraction of these arteries in response to diet-induced obesity was associated with reduced acetylcholine-mediated vasorelaxation [82] linking chemerin and vascular endothelial function. The underlying mechanism appears to involve a reduction in NO bioavailability as incubation of rat aortic rings with chemerin reduced NO function and enhanced ROS generation [83]. Indeed, chemerin level in non-diabetic obese humans negatively correlates with paraoxonase-1, which is a potent antioxidant implicated in cardiovascular disease risks [84]. Expression of the chemerin receptor in endothelial cells is increased in response to inflammatory signaling arising from interleukin signaling (IL-1β and IL-6) and TNFα [85] and in humans, plasma serum chemerin levels were found to correlate strongly with cytokine production (IL-6, TNFα, and leptin) [86].

Arterial stiffening in obesity

Arterial stiffening is considered an independent predictor of cardiovascular disease [8789]. Stiffening of the vasculature is a hemodynamic adaptation to maintain end-organ perfusion in the presence of increased arterial pressure. Arterial stiffness is commonly associated with the vascular consequences of obesity [90], but is influenced by a variety of factors such as stress, diet, and physical activity [91,92]. Interestingly, in obesity arterial stiffness displays regional variability depending on which vascular bed is examined [93]. This is likely due to timing effects and the local vascular gene programming within each specific vascular bed. A recent elegant study by Weisbrod and colleagues defined the time course of vascular alterations in response to obesity in mice [94]. Arterial stiffness was found to be increased as early as 1 month after high fat/high sucrose diet feeding and this preceded both the vascular endothelial dysfunction and the elevation in systolic blood pressure [94]. Furthermore, weight loss induced by switching obese mice from high fat/high sucrose diet to normal diet normalized both arterial stiffness and blood pressure supporting the plasticity of the vascular alterations evoked by high-fat feeding and accumulation of fat mass [94].

Excessive activity of the sympathetic nervous system is a hallmark of obesity [9], and sympathetic overactivity promotes inflammatory signaling [95]. Inflammation signaling pathways have been implicated in the development of arterial stiffening through cytokines such as MCP-1, TNFα, and the interleukin family of cytokines notably IL-1, IL-6, and IL-17 [96]. Recently, Wu and colleagues demonstrated that mice lacking the inflammatory cytokine IL-17a are protected against aortic stiffening in response to chronic angiotensin II infusion [97]. Conversely, mice overexpressing Il-17a exhibit endothelial dysfunction and arterial hypertension [98]. In obesity, IL-17a expression was found to be elevated in visceral adipose tissue isolated from obese women [99]. However, it is currently unclear whether IL-17a plays a role in the arterial stiffening associated with obesity.

Adoptive T-regulatory lymphocytes (Tregs) have recently been demonstrated to provide positive effects on arterial stiffness through anti-inflammatory signaling [100]. Adoptive transfer of Tregs protected mice from angiotensin II-induced increase in blood pressure, arterial stiffness, plasma levels of TNFα, IL-6, and interferon-γ as well as the elevated expression of mesenteric artery adhesion molecules [100]. Furthermore, evidence in both obese human and mice demonstrate that the anti-inflammatory lymphocytes are decreased [101,102]. Whether adoptive transfer of these anti-inflammatory T-regulatory lymphocytes into obese subjects can ameliorate the arterial stiffness and vascular dysfunction similar to the animal models remains to be determined [97,98,100].

In addition to inflammatory signaling, vascular oxidative stress plays a major role in the regulation of arterial stiffening in normal physiological state as well as in obesity. Serum levels of prooxidants such as myeloperoxidase [103] and plasma levels of isoprostane [104] are significantly elevated in obese humans compared with their lean counterparts. These circulating prooxidants have been found to strongly correlate with indices of arterial stiffening in humans [105]. In animal models of obesity such as mice fed a high fat/high sucrose diet, Weisbrod and colleagues found that increased vascular oxidative stress led to oxidative modification of the Ca2+-dependent ATPase (SERCA) pump impairing vascular relaxation responses [94]. This decreased ATPase activity in combination with the reduced NO dilatator function in this mouse model further point to the increased vascular oxidative stress as a contributor to arterial stiffening in the context of obesity.

Recently, a study in high-fat diet fed female mice demonstrated that a mineralcorticoid antagonist, spironolactone, can prevent both the oxidative stress and vascular inflammation associated with obesity through a mechanism involving ERK signaling in the smooth muscle [106]. Additionally, using a transgenic smooth muscle specific p22 NADPH subunit overexpressing mouse model, Wu et al. demonstrated significant aortic stiffening and increased blood pressure in response to increased oxidant stress generated in this model [36]. It is clear that the elevated oxidant status in the vasculature contributes to the development of arterial stiffening in response to hypertension and obesity. It would be of great interest to determine if blockade of vascular oxidative stress in obesity could prevent the increased aortic stiffening associated with high fat diet-induced obesity.

The role of metabolic and energy controlling hormones in the regulation of aortic stiffness remains largely unexplored. Arterial stiffness is increased in ob/ob mice suggesting that leptin deficiency or leptin resistance (as in common obesity) may contribute to arterial stiffening [107]. Treatment of ob/ob mice with leptin resulted in improved aortic compliance compared with ob/ob mice that undergo caloric restriction indicating that arterial stiffness in these mice is due to leptin deficiency [107]. Additionally, treatment of wild-type mice with a leptin receptor antagonist resulted in an increase in aortic stiffness without any change in body weight or arterial pressure [107] further supporting a role for leptin signaling in the regulation of arterial compliance and stiffness.

Vascular effects of weight loss

It is clear that one of the strongest predictors of hypertension in humans regardless of sex, age, or race is excess adiposity [10]. Several studies have demonstrated that the vascular complications associated with obesity are highly plastic in nature and that weight loss can partially or completely reverse the deleterious hemodynamic and vascular consequences of obesity [108]. Indeed, overweight/obese humans that lost weight displayed significant improvements in brachial artery flow-mediated dilation and changes in forearm blood flow indicating improved vascular endothelial function [69]. In this study, infusion of L-NG-nitroarginine methyl ester (L-NAME), an NO synthase inhibitor, attenuated the weight loss-induced improvement in endothelial function highlighting the importance of NO bioavailability as a major underlying mechanism of the vascular beneficial effects of weight loss (Figure 1).

Recently, Padilla and colleagues used high fat fed female mice to demonstrate that regular aerobic exercise can partially ameliorate endothelial cortical stiffening independenlyt of changes in aortic stiffness measured via pulse wave velocity [109]. Similarly, obese human subjects that achieved significant weight loss exhibited a reduction in aortic stiffening [110]. Thus, lifestyle modifications to promote weight loss through proper diet and exercise can positively affect and reverse the impaired endothelial function and arterial stiffening in obesity.

Another promising strategy for the management of obesity and metabolic syndrome relates to targeting the PVAT and its inflammatory signaling pathways. In humans, weight loss induced by bariatric surgery restores the anticontractile vascular properties of the PVAT in small arteries 6 months after surgery [111]. These changes were associated with reduction in the inflammatory cytokine expression and enhancement in NO bioavailability within the vasculature likely through a ROS-mediated mechanism as treatment of vessels of obese patients with free radical scavengers restored vascular function [111]. Similarly, obese human subjects that underwent 12 weeks of dietary intervention displayed increased plasma nitrite levels indicative of improved NO bioavailability [112]. Weight loss intervention as a therapeutic approach to obesity-associated vascular dysfunction is further supported by animal studies. In mice, weight loss induced by caloric restriction reverses obesity-induced dysfunction in the PVAT, increases eNOS expression, decreases TNFα expression and macrophage infiltration [113].

It is clear that managing adipose tissue especially visceral fat tissue has beneficial effects on the vasculature and that this management may be a useful strategy for the prevention and treatment of the cardiovascular risks associated with obesity. Notably, the vascular changes linked to obesity can be partially reversed or ameliorated by weight loss even after they are established. However, the efficacy of weight loss on vascular function requires more clinical studies to determine effectiveness in various human populations. Finally, it may be worth exploring the possibility of targeting the vascular inflammatory signaling pathways that are up-regulated in obesity as a potential therapeutic approach to the vascular dysfunction associated with this condition.

Conclusions and perspectives

Vascular dysfunction associated with obesity and the resulting cardiovascular sequelae are serious risk factors affecting a constantly rising portion of the worldwide population. Recent evidences have further implicated the combinatory role of oxidant and inflammatory signaling as a critical underlying mechanism of vascular changes in obesity. Targets of these responses in obesity include the vasculature and the surrounding PVAT that are key players in the pathogenesis of obesity. Further research in these areas is warranted to improve our understanding of these pathways that may lead to the identification of new pharmacological tools to treat the cardiovascular risks and end-organ damage associated with obesity.

Despite recent advances in our understanding of the complex interplay between altered vascular signaling pathways and prooxidant/inflammatory mechanisms there are several remaining issues that need to be addressed. First, there is a need to dissect the complex and integrated signals that underlie the cross-talk between the PVAT and the vasculature and better characterize the adipokines and other factors involved. Second, a more complete appreciation of the timing and mechanisms accounting for the shift of the PVAT from being vasculoprotective to having detrimental effects as adiposity increases is crucial. In addition to the possibility of harnessing such knowledge for therapeutic purposes, it will improve understanding of the plasticity of the vasculature. Finally, clinical trials aimed at assessing the efficacy of currently available drugs to reverse the cardiovascular risks associated with obese individuals are highly warranted.

Funding

The work was supported by the US National Institutes of Health [grant number HL084207]; the American Heart Association [grant number #14EIA18860041]; the University of Iowa Fraternal Order of Eagles Diabetes Research Center; the University of Iowa Center for Hypertension Research; and American Heart Association [grant number #16POST30830004 (to J.J.R.)].

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • BBS

    Bardet Biedl syndrome

  •  
  • BMI

    body mass index

  •  
  • eNos

    endothelial nitric oxide synthase

  •  
  • FFA

    free fatty acids

  •  
  • IL-6

    interleukin-6

  •  
  • iNOS

    indicible nitric oxide synthase

  •  
  • L-NAME

    L-NG-nitroarginine methyl ester

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MCP-1

    monocyte chemoattractant protein 1

  •  
  • NO

    nitric oxide

  •  
  • PI3K

    phosphaditylinositol-3 kinase

  •  
  • PVAT

    perivascular adipose tissue

  •  
  • RAAS

    renin–angiotensin–aldosterone system

  •  
  • ROS

    reactive oxygen species

  •  
  • SNP

    sodium nitroprusside

  •  
  • SOCS3

    suppressor of cytokine signaling 3

  •  
  • TNFα

    tumor necrosis factor α

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