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. 2012 Feb;165(3):591–602. doi: 10.1111/j.1476-5381.2011.01472.x

Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction

Matthias Barton 1, Oliver Baretella 1,2, Matthias R Meyer 1,3
PMCID: PMC3315033  PMID: 21557734

Abstract

Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the world's population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease, obesity has deleterious effects on metabolic homeostasis, and affects numerous organ systems including heart, kidney and the vascular system. Thus, obesity is now regarded as an independent risk factor for atherosclerosis-related diseases such as coronary artery disease, myocardial infarction and stroke. In the arterial system, endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium-derived vasoactive factors favouring vasoconstriction, cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally, because of the similarities of the vascular pathomechanisms activated, obesity can be considered to cause accelerated, ‘premature’ vascular aging. Here, we will review some of the pathomechanisms involved in obesity-related activation of endothelium-dependent vasoconstriction, the clinical relevance of obesity-associated vascular risk, and therapeutic interventions using ‘endothelial therapy’ aiming at maintaining or restoring vascular endothelial health.

LINKED ARTICLES

This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3

Keywords: diet, obesity, adipocytes, fat, elderly, hypertension, disease, diabetes

Endothelium-dependent regulation of vascular tone

Endothelial cells form the inner lining of arterial and venous blood vessels and lymphatic vessels which amount to approximately 1.5 kg in a person weighing 70 kg, covering an area of approximately four tennis courts (Cryer, 1983; Luscher and Barton, 1997; Barton, 2006). Under normal conditions, endothelial cells constantly produce vasoactive and trophic substances that control inflammation, vascular smooth muscle cell growth, vasomotion, platelet function, and plasmatic coagulation (Barton and Haudenschild, 2001; Traupe et al., 2003). In the early 1970s, Ross and Glomset reported that endothelial cells protect smooth muscle cells to proliferate, which generated the ‘response-to-injury’ theory of atherosclerosis (Ross and Glomset, 1973). The importance of endothelial cells as both source and target of vasoactive factors, however, was discovered by Robert F. Furchgott around 30 years ago (Furchgott and Zawadzki, 1980; Nilius et al., 2010; Barton, 2011). Since then, physiological roles of these factors have been demonstrated (Furchgott and Vanhoutte, 1989) as well as that these factors both contribute to and interfere with the development of cardiovascular disease (Barton and Haudenschild, 2001; Traupe et al., 2003; Barton, 2010; Vanhoutte, 2011). Finally, the new field of endothelial cell research eventually allowed the development of the first class of drugs specifically targeting an endothelial vasoconstrictor, the endothelin receptor antagonists (Barton, 2011).

Endothelium-dependent vasoconstriction: balancing endogenous vasodilation

Vasoactive factors derived from endothelial cells include the vasodilating gas NO, oxygen-derived free radicals such as ·O2- or ·OH, or peptides such as endothelins and angiotensins (Feletou and Vanhoutte, 2006). Thus, endothelium-derived mediators have either endothelium-derived relaxing factor (EDRF) or endothelium-derived contracting factor (EDCF) functions (Vanhoutte and Tang, 2008; Vanhoutte, 2009b). Endothelial cells also synthesize cyclooxygenase-derived EDCFs and EDRFs, and EDHFs (endothelium-derived hyperpolarizing factors) (Busse et al., 2002; Feletou and Vanhoutte, 2006). Endothelial factors are formed by enzymes such as NO synthase, NADPH oxidases, cyclooxygenases, converting enyzmes and epoxigenases, among others (Feletou and Vanhoutte, 2006). Although termed ‘endothelial’ factors, these mediators are not exclusively formed by endothelial cells, but also synthesized by other cells such as vascular smooth muscle cells, inflammatory cells such as leukocytes, mesangial cells or adipocytes, all of which appear to be centrally involved in obesity-related disease processes (Xu et al., 2003; 2010; Rocha and Libby, 2009; Li et al., 2010). An excessive production or increased activity through specific receptors causes endothelial factors to induce vasoconstriction and vascular cell growth (Luscher and Barton, 1997). The numerous endothelial factors identified so far have been extensively studied under physiological and pathophysiological conditions (reviewed in Vanhoutte et al., 2009; Barton, 2010; 2011).

Endothelium-derived vasoconstrictors: prostanoids, superoxide and endothelin

Arachidonic acid-derived vasoconstrictor prostanoids were the first EDCFs identified by DeMey and Vanhoutte (Vanhoutte and Tang, 2008; Vanhoutte, 2009a; Barton, 2011; Vanhoutte, 2011) shortly after the report of endothelium-dependent dilation (Furchgott and Zawadzki, 1980), demonstrating contractile effects mediated by endothelium-derived cyclooxygenase products (De Mey and Vanhoutte, 1982; Wong and Vanhoutte, 2010). Superoxide anion, a short-lived by-product of oxidative metabolism, was also found to have vasoconstrictor activity again by Vanhoutte's group (Rubanyi and Vanhoutte, 1986) and also by Moncada and associates (Gryglewski et al., 1986). This constrictor effect is largely due to the EDRF/NO-inactivating properties of superoxide anion (Rubanyi and Vanhoutte, 1986). Reactive oxygen species have been studied since the early 1990s and Griendling and coworkers have identified a vascular NADPH oxidase as one of the major sources of vascular reactive oxygen species (Griendling et al., 2000); the nox4 isoenyzme is mainly expressed in endothelial cells (Brandes et al., 2010). Interestingly, EDHF synthase/cytochrome P450 expoxygenase is also a source of superoxide anion (Fleming et al., 2001). In the 1980s, several groups reported the release of a vasoconstrictor substance from cultured endothelial cells (Hickey et al., 1985; Gillespie et al., 1986; O'Brien et al., 1987). Investigators had accidentally detected its peptidergic vasoconstrictor activity in experiments in search of the vasodilator molecule then called EDRF (Rubanyi, 2011 and Dr David M. Pollock, pers. comm.). This ‘EDRF’ was later identified as the gas NO (Ignarro et al., 1987; Furchgott, 1988). The gene and peptide sequence of the vasoconstrictor peptide, named endothelin due to its cellular origin, was ultimately revealed by Masaki's group from Japan and published in 1988 (Yanagisawa et al., 1988; Barton and Yanagisawa, 2008). Subsequently, other members of this peptide family such as endothelin-2 and endothelin-3 were identified (Barton and Yanagisawa, 2008). Through activation of ETA receptors, endothelin-1 (ET-1) causes sustained and potent vasoconstriction and also activates cell proliferation (Barton and Yanagisawa, 2008) and mediates endothelium-dependent contractions via thomboxane A2 (Taddei and Vanhoutte, 1993; Moreau et al., 1996; d'Uscio et al., 1997; Traupe et al., 2002a). As with other vasoconstrictors, NO counterbalances the effects of endothelin (Vanhoutte, 2000). Recently, Yanagisawa's group reported that endothelial cell-derived ET-1 is responsible for the majority of endothelin tissue expression, as endothelial cell-specific prepro-ET-1-deficient mice exhibit a reduction of ET-1 tissue levels in several organs up to 70% compared with wild-type mice (Kisanuki et al., 2010). The hypotension observed in animals with endothelial cell-restricted endothelin deficiency also indicates that the vasoconstrictor activity of endogenous endothelin peptide – via the ETA receptor – outweighs its ETB -mediated dilator activity.

Obesity, insulin resistance and diabetes: vascular inflammtion as key event

In the 21st century, obesity has become the main cause of diabetes and associated diseases. Already in overweight patients, abnormalities found in obese individuals are present, albeit to a lesser degree. As a direct consequence of the disease, obese patients present with enhanced sympathetic drive, increased vasomotor tone and hypertension; they develop metablic abnormalties such as insulin resistance, dyslipidaemia and diabetes, and organ injury such as fatty-inflammatory degeneration of the liver (non-alcoholic steatohepatitis) and structural injury of the kidney through focal–segmental glomerulosclerosis (Abate et al., 2001; Visscher and Seidell, 2001). Moreover, overweight or obese individuals are at a higher risk to develop left ventricular (Russo et al., 2011) and right ventricular (Wong et al., 2006) diastolic dysfunctions, and to develop heart failure due to obesity cardiomyopathy in the course of the disease (Russo et al., 2011; Wong and Marwick, 2007). Because the metabolic impairments in obesity often deteriorate in overt diabetes, prevention of obesity is of paramount importance. Diabetic complications are now recognized as some of the most frequent causes of organ failure due to cardiovacular causes (myocardial infarction and heart failure), cerebral disease (stroke), renal failure/requirement for dialysis or renal transplant therapy (Farag and Gaballa, 2010; Dunlay et al., 2011; Herman, 2011; Ratner and Sathasivam, 2011), or peripheral vascular disease (Skilton et al., 2011). The mechanisms involved in the disease accelleration by obesity and/or diabetes involve various mechanisms (Visscher and Seidell, 2001), with generalized inflammation being the main unifying principle of disease (Wellen and Hotamisligil, 2003; 2005); importantly, these changes are aggravated in women after menopause where cessation of oestrogen production accelerates the development of obesity, diabetes and hypertension (Barton and Meyer, 2009; Meyer et al., 2011). Impairment of glucose and insulin function are central to the metabolic abnormalities found in obesity (Wellen and Hotamisligil, 2003; 2005). They are, however, not only restricted to the endocrine pancreas and skeletal muscle but also directly involve secretion of proteins from fat tissue that are involved in maintaing adipocyte function, and, if abnormally increased, may directly worsen metabolism, inflammation, endothelial cell dysfunction and organ injury (Ouwens et al., 2010; Zhang et al., 2010; Cui et al., 2011). The so-called adipokines (or adipocytokines), for which disease-modifying roles in obesity have been demonstrated, include adiponectin, leptin and ghrelin (Ouwens et al., 2010; Zhang et al., 2010; Cui et al., 2011). For some of these proteins, direct effects on insulin signalling, fat cell growth and inflammation have been demonstrated (reviewed in Ouwens et al., 2010; Zhang et al., 2010; Cui et al., 2011).

Obesity: a trigger of endothelial cell injury and amplifier of cardiovascular risk

Within only a decade, obesity has become one of the most relevant global health issues (McLellan, 2002; Barton and Furrer, 2003), with the associated health costs exploding (Finucane et al., 2011; Heidenreich et al., 2011). Six years ago, 1.6 billion adults worldwide were diagnosed as overweight, and 400 million were obese. Within only another 4 years, the numbers worldwide will have increased to 2.3 billion adults being overweight and 700 million being obese (Stewart et al., 2008; 2009; Malik et al., 2010), representing an alarming 10-year increases of 44 and 75%, respectively. Most recent studies confirm that the body mass index continues to increase on almost all continents (Finucane et al., 2011). The reasons for this development are economic growth in developing countries as well as changes in nutrition patterns, in combination with the availability of inexpensive and unbalanced diets rich in carbohydrates and fat (Bray and Popkin, 1998; McLellan, 2002; Stewart et al., 2008; 2009; Malik et al., 2010). Excess food intake is further aggravated by an unfavourable lifestyle; lacking physical exercise; and consuming high caloric, non-alcoholic and alcoholic drinks (Barton and Furrer, 2003; Malik et al., 2010). Excessive amounts of visceral fat are now recognized as one of the major contributors of the obesity-associated organ injury, and studies in rodents and in monkeys indicate that either removal of visceral fat or caloric restriction can substantially extend lifespan in mammals (Muzumdar et al., 2008; Colman et al., 2009). Obesity, diabetes and aging share a number of the same etiopathologies that contribute to endothelial and vascular injury (Barton, 2010). One of the most worrisome developments is that obesity now increasingly affects school children (Jolliffe, 2004) (Ludwig, 2007) who – at a young age – present with diseases normally found only in adults of higher age, namely arterial hypertension and diabetes mellitus (Barton and Furrer, 2003). Overweight children prematurely develop abnormal endothelial cell function and thickening of the arterial vascular wall (Woo et al., 2004), as well as myocardial wall thickening (de Jonge et al., 2011), features usually observed only in obese adults or aged individuals (Steinberg et al., 1996). Indeed, a most recent paper concluded that obesity induces premature cardiac aging in younger patients (Niemann et al., 2011). This further underscores that obesity actually mimics (and thus accelerates) normal aging in many aspects, also evident from the increased intima-media thickness found in obese young adults (Berni et al., 2011). This once more illustrates the importance to actively intervene and start obesity prevention as early as possible to interfere with its cardiovascular consequences (Barton and Furrer, 2003).

Evidence for endothelium-derived vascoconstriction in obesity

Endothelium-derived vasoconstrictor prostanoids/EDCF

Enhanced vasoconstriction has been observed in patients with obesity (Sivitz et al., 2007), and both cyclooxygenase and endothelin have been implicated in these responses. In mice with diet-induced obesity, formation of endothelial vasoconstrictor prostanoids is enhanced in both aorta and carotid artery (Traupe et al., 2002b) (Figure 1); these contractions are fully blocked by non-selective COX-inhibition or antagonists of thromboxane receptors (Figure 1C), but not COX-2 selective inhibitors (Traupe et al., 2002b). In an elegant study, Tang et al. subsequently demonstrated using COX-1- and COX-2-deficient mice that COX-1 is indeed the sole enzyme mediating prostanoid-mediated EDCF production in mice (Tang et al., 2005). Results from studies in mice on high-fat diet suggest activation of COX-1-dependent vasoconstrictor pathways in obesity and that these pathways contribute to enhanced vasoconstriction also observed in obese humans (Cardillo et al., 2004; Rask-Madsen and King, 2007) (Figures 1 and 2). Similar to obesity, activation of COX-dependent pathways has been reported to occur with aging (Tang and Vanhoutte, 2008), again suggesting common pathways between both physiopathologies. Recent work comparing functional vascular injury due to obesity in youth and adulthood indeed suggests that obesity causes changes compatible with accelerated, ‘premature’ vascular aging with regard to endothelium-dependent, prostanoid-mediated contractlity (Bhattacharya et al., 2008a). In addition to COX-derived EDCFs activating thromboxane receptors, another endothelium-derived arachidonic acid product, prostacylin (which can also act as an EDCF) (Vanhoutte, 2011), has recently been directly implicated in obesity, by determining the fate for development of fat cells from progenitor cells (Ishibashi and Seale, 2010; Vegiopoulos et al., 2010).

Figure 1.

Figure 1

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Effect of diet-induced obesity (•) on acetylcholine-mediated, endothelium-dependent vasoreactivity in the carotid artery (A, C) and thoracic aorta (B) of C57 mice. Controls (○) were fed a normal chow diet. In the carotid artery, diet-induced obesity impairs NO-mediated endothelium-dependent relaxation while at the same time enhancing endothelium-dependent contractions in the carotid artery (A). In the aorta, the larger conduit vessel, NO-dependent dilation is preserved during obesity; however, endothelium-dependent contractions now become visible (B). *P < 0.05 vs. C57 control. Panel C shows three original recordings of responses to acetylcholine in norepinephrine-precontracted carotid artery rings from the same obese C57 animal after 30 weeks on high-fat diet in the absence of inhibitors (upper tracing), in the presence of the thromboxane receptor antagonist SQ-30741 (middle tracing) or the cyclooxygenase inhibitor indomethacin (bottom tracing). Transient, endothelium-dependent contraction responses to acetylcholine are visible beginning at concentrations of 30 nmol·L−1 in the untreated carotid artery ring, whereas inhibition of either thromboxane receptors (SQ-30741) or cyclooxygenase (indomethacin) completely abrogates endothelium-dependent contractions. NE indicates norepinephrine, arrows indicate administration of increasing cumulative concentrations of acetylcholine (mol·L−1), ‘w’ indicates wash-out. Figure panels A an B are adapted from Traupe et al., 2002b and reproduced with permission of the publisher.

Figure 2.

Figure 2

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Effect of 30 weeks of diet-induced obesity in placebo-treated (Inline graphic) or endothelin ETA-receptor antagonist-treated (Inline graphic) C57 mice on endothelium-dependent contractions to acetylcholine (30 µmol·L−1) in NO-depleted vascular rings of aorta (A) and carotid artery (B). Contractions to angiotensin II in the aorta are depicted on the right (C). Depletion of endothelium-derived NO was achieved by acute treatment with L-NAME (300 µmol·L−1), a non-selective inhibitor of NO synthases. In NO-depleted arteries of control animals on chow diet (□), EDCF were only present in the carotid artery. In mice with diet-induced obesity (Inline graphic), the residual relaxation to acetylcholine is converted into a contraction in the aorta, and the magnitude of EDCF-mediated contractions was doubled in the carotid artery. Chronic treatment with the orally active endothelin ETA receptor antagonist darusentan (LU135252) (Inline graphic) – without affecting body weight – not only completely prevented enhanced EDCF-mediated contractions, but also caused acetylcholine to elicit a small relaxation instead (B). Similarly, in NO-depleted aortic rings, contractions to angiotensin II (0.1 µmol·L−1) were markedly enhanced by obesity (Inline graphic), an effect again completely abrogated after chronic endothelin receptor antagonist treatment which had no effect on obesity (Inline graphic). *P < 0.05 versus control; †P < 0.05 versus obesity. Panels A and B: This research was originally published in Clinical Science. Traupe et al., 2002a. © Portland Press Limited. Panel C is from Barton et al., 2000b, and reproduced with permission of the American Heart Association and the publisher.

Endothelium-derived angiotensin II

Obesity activates the renin-angiotensin-aldosterone system (RAAS) (reviewed in Barton et al., 2003a). Similar to what occurs during aging (Barton et al., 1997), obesity does not equally affect all vascular beds to the same degree. In the C57 mouse model of diet-induced obesity (Surwit et al., 1988), contractions to angiotensin II markedly increase only in the aorta (Figure 3C, filled bar) but not in the carotid artery (Barton et al., 2000b). Chronic treatment with an orally active endothelin ETA receptor antagonist (darusentan) completely abrogated the increased contractility (Barton et al., 2000b) (Figure 3C, hatched bar), indicating a molecular interaction between these two vasoactive systems and their cellular targets. These effects were independent of body weight and arterial blood pressure, compatible with the notion that endogenous endothelin becomes activated during obesity and that endothelin – at least partially – contributes to angiotensin-mediated vasoconstriction in certain vascular beds. Contractility to angiotensin in this model was also blocked by cyclooxygenase inhibition in vitro to a large degree, suggesting that – unlike in other species – in the mouse vasculature, endothelial EDCFs formed from vasoconstrictor prostanoids largely contribute to responses elicited by other vasoconstrictors (Barton et al., 2000b). This effect appears to develop with age (Kretz et al., 2006). Obesity also increases protein expression of the main cellular target of angiotensin II, the AT1 receptor, which is up-regulated only if the diet contained high amounts of fat (Mundy et al., 2007b).

Figure 3.

Figure 3

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Anatomic heterogeneity of ET-1 mediated vascular contractility in C57 mice. The magnitude of contractions to ET-1 in the carotid artery (A) was twice that of the aorta (B), yet diet-induced obesity augmented ET-1-induced contractions only in aorta (B) but not the carotid artery (A). Western blot experiments of aortic expression of ETA receptor; total ERK1/2 protein was used as loading control. Diet-induced obesity substantially increases aortic endothelin ETA receptor expression, whereas ERK1/2 protein remains unafffected (C). *P < 0.05 versus control. Figure panels are in part adapted from Traupe et al., 2002b (Panels A and B) and Mundy et al., 2007b; 73:368–375 (Panel C). Figures are reproduced with permission of the publishers.

Endothelium-derived ET-1

As recently shown by Yanagisawa and co-workers, endothelium-derived endothelin contributes to the majority of endothelin found in different organs and in plasma, and also is important for maintaining basal blood pressure (Kisanuki et al., 2010). Endothelin production not only is regulated by angiotensin II both in vitro and in vivo (reviewed in Lüscher and Barton, 2000), but diet-induced obesity also up-regulates renal (but not pulmonary) ACE activity in an ETA receptor-dependent manner (Barton et al., 2000b). Again, this suggests that both the RAAS and the endothelin system interact with each other in a positive feedback loop (Barton et al., 2000b). The data also indicate – that under certain conditions such as obesity – endothelin receptor antagonists exert ACE inhibitor-like activity (Barton et al., 2000a). One of the most important factors responsible for the high prevalence of obesity is an increased intake of high-calorie food rich in carbohydrates and fat (Bhattacharya et al., 2008a). Several experimental models of diet-induced obesity are available (Surwit et al., 1988; Tschop and Heiman, 2001; Collins et al., 2004) in which changes in the vasculature and kidney have been studied. Experimental studies suggest that these animal models exhibit many of the changes seen with obesity in humans, including inflammation, dyslipidaemia and abnormalities of vasomotor tone (Surwit et al., 1988; Tschop and Heiman, 2001; Traupe et al., 2002b; Collins et al., 2004). Indeed, like in humans (Cardillo et al., 2004), vascular responses to endothelin are enhanced in both models of diet-induced (Figure 3) and monogenetic leptin-deficient obesity (Traupe et al., 2002a,b; Mundy et al., 2007a,b; Bhattacharya et al., 2008b). Importantly, the susceptibility to the obesity-enhanced responsivness to ET-1 varies between vascular beds (Figure 3), an anatomic heterogeneity that could also be of relevance for the arterial circulation of obese humans. In addition to its vasoconstrictor function ET-1 is a potent pro-atherogenic peptide (Barton et al., 2003b), which likely plays a role in the increased vascular risk seen with obesity (Barton, 2010). Indeed, with obesity vascular ET-1 expression increases at the mRNA level in the vasculature (Traupe et al., 2002b) and at the peptide level in the kidney (Barton et al., 2000b). Obesity-induced increases of vascular protein levels of the main target of ET-1, the ETA receptor (Mundy et al., 2007b), have also been reported (Figure 3C). Thus, the experimental studies provide some mechanistic explanation (Figure 2) why diet-induced obesity exerts specific changes promoting enhanced vasoconstriction similar to what can be seen in obese humans with regard to an activated endothelin pathway (Cardillo et al., 2004). Clinical studies using endothelin receptor antagonists (ERAs) also indicate beneficial metabolic effects (Shemyakin et al., 2006; 2010; Ahlborg et al., 2007) and suggest possible therapeutic potential for endothelin receptor antagonists in patients with obesity (Barton et al., 2003a). Recent studies also suggest therapeutic potential for obesity-related renal complications such as proteinuria (Barton, 2008; Thoenes et al., 2009). In fact, three clinical studies in obese patients with kidney disease (Weber et al., 2009; Kohan et al., 2010; 2011; Mann et al., 2010) have been recently published, showing a reversal of functional renal injury after endothelin blockade.

Endothelium-derived free radicals and inactivation of NO

Several studies in experimental animals and humans have shown that in obesity, the bioactivity of NO is reduced (Bender et al., 2007; Rask-Madsen and King, 2007; Bourgoin et al., 2008; Damjanovic and Barton, 2008). The mechanistic concept that has been mostly propagated is the inactivation of NO by superoxide anion (O2-), leading to formation of peroxynitrite. The source of increased O2-production is not only enzymes such as NADPH oxidase, but also uncoupled NO synthase (Forstermann and Munzel, 2006; Martins et al., 2010). Increased nitrotyrosine formation as a consequence of peroxynitrite production has been described in obese animal models (Brodsky et al., 2004; Galili et al., 2007; Bourgoin et al., 2008). More recently, other pathways such as guanylate cyclase, the intracellular target of NO, have also been shown to be affected by obesity and have been directly linked to inflammation (Rizzo et al., 2010). Due to the fact that NO is formed by the multi-enzyme complex NO synthase (Förstermann et al., 1994), which concomitantly produces reactive oxygen species such as superoxide anion through its NADPH oxidase domain, increasing NO bioactivity has been complicated by NO synthase uncoupling (Wever et al., 1997; Stroes et al., 1998; Landmesser et al., 2003). As the reaction between NO and superoxide anion is essentially diffusion limited, substantial amounts of peroxynitrite (ONOO-) are formed (Barton, 2010). ONOO- causes cell injury through the nitrosylation of proteins which partially or completely inactivates them (Abello et al., 2009). Nitrosylation of proteins, which will cause relatively stable nitrotyrosine to be formed, will change the function, structure, and thus the ability of these proteins to interact with other proteins (Musci et al., 2006). In addition to superoxide anion and peroxynitrite, vascular formation and activity of other oxygen derived radicals are altered in obesity. In lean control mice and mice with monogenetic obesity (Mundy et al., 2007a), ET-1 stimulates hydroxyl radical formation, an effect that is more or less abolished by obesity (Mundy et al., 2007a). However, relaxant responses to hydroxyl radical are enhanced in animals with monogenetic obesity (Mundy et al., 2007a). Similar observations were made in models of diet-induced obesity, where vascular responses to hydroxyl radical changed from contraction in lean animals into relaxation upon obesity induction, again effects being specific to certain vascular beds (Bhattacharya et al., 2008b).

Endothelium-derived peptides neuropeptide y and atrial natriuretic peptides

Neuropeptide Y, a centrally acting peptide involved in appetite regulation (Achike et al., 2011; Kim et al., 2010), has been recently shown to stimulate adipogenesis (Baker et al., 2009). Neuropeptide Y binds to endothelial cells, causes NO-dependent dilation, stimulates endothelial cell growth and affects endothelial cell macromolecule permeability (Sanabria and Silva, 1994; Noll et al., 1996; Marion-Audibert et al., 2000; Nilsson et al., 2000). Although a role for neuropeptide Y in adipogenesis and endothelial cell function – including enhanced thromboxane/EDCF-mediated vascular tone (Fabi et al., 1998) – has been demontrated, no data showing its involvement in obesity-associated vascular dysfunction have been published. Another group of peptides are the atrial natriuretic peptides ANP, BNP, and CNP, which have been recently implicated in obesity and lipid mobilization (Bartels et al., 2010; Chen-Tournoux et al., 2010; Koppo et al., 2010; Saritas et al., 2010). Atrial natriuretic peptides are also formed and metabolized by endothelial cells (Johnson et al., 1990; Lew and Baertschi, 1992; Sugiyama et al., 1995; Yamada and Yokota, 1996). CNP causes endothelium-independent and endothelium-dependent relaxation (Evans et al., 1993; Barton et al., 1998; Chauhan et al., 2003; Villar et al., 2007; Leuranguer et al., 2008; Liang et al., 2010), yet direct effects of obesity on endothelial-cell dependent responses or activities of atrial natriuretic peptides have not been reported.

Therapeutic interventions for patients with obesity: ‘endothelial therapy’

A decade ago, we coined the concept of ‘endothelial therapy’ as a means to preserve and/or improve vascular function by reducing production of deleterious endothelium-derived mediators in order to attenuate atherosclerosis progression (Barton and Haudenschild, 2001). Generally, either increasing cellular antioxidant capacity or reducing oxidative stress will have similar beneficial effects on the vasculature. Beneficial effects of interventions to reduce oxidative stress and inflammation (Figure 4) have been shown, among others, for diseases such as atherosclerosis, myocardial infarction, stroke, peripheral vascular disease, arterial hypertension, chronic renal failure, pulmonary arterial hypertension (Vanhoutte et al., 2009), and for a number of disease conditions mainly associated with chronic inflammation such as connective tissue diseases and metabolic conditions such as insulin resistance and diabetes (Libby, 2005; Rocha and Libby, 2008; 2009; Agouni et al., 2009). A number of modalities are available to interfere with obesity-related changes in endothelial cell function (Jensen-Urstad et al., 1999). Preventive measures, which must be applied already to children and adolescents, should include maintaining normal body weight (or weight reduction, if required) and avoiding unbalanced diets rich in fat and sugars and low in fibres (Chen et al., 2010). Equally important appears to be the ‘therapeutic’ role of regular physical activity, which reduces the incidence and prevalence of the obesity-related co-morbidities diabetes, hypertension, dyslipidaemia and depression (Colditz, 1999; O'Brien and Dixon, 2002; Barton, 2010). Regular intense exercise in humans has beneficial effects on cardiovascular health showing a dramatic risk reduction (Manson et al., 2002), which appears to be maintained even in the presence of obesity. Similarly, weight loss has been shown to improve the vascular risk profile, including a reduction of aortic pulse wave velocity (Rider et al., 2010). In humans, endothelium-dependent vasoreactivity can be preserved by exercise even at a high age (Jensen-Urstad et al., 1999). Obesity is highly prevalent among elderly individuals (Bramlage et al., 2004), as is arterial hypertension, dyslipidemia and atherosclerosis (Barton and Furrer, 2003; Bramlage et al., 2004). Unfortunately, these conditions are no longer restricted to elderly individuals but already present to a considerable degree in children (Barton and Furrer, 2003; Ludwig, 2007). It will thus require immediate action and intervention to avoid future disease in adulthood. This is of particular importance in view of the fact that childhood obesity – even if normal body weight is achieved later in life – has been linked to an increased likelihood of adult coronary artery disease (Baker et al., 2007; Bibbins-Domingo et al., 2007; Ludwig, 2007).

Figure 4.

Figure 4

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Role of endothelium-derived vasoconstrictors for atherogenesis. Shown are levels and localization of the endothelial vasoconstrictors and growth factors ET-1, prostanoid endothelium-derived vasoconstricting factor/thromboxane A2/prostaglandin H2 (EDCF), angiotensin II (Ang II) and supoxide anion (O2−) in health (left), obesity/pre-diabetes (middle) and overt diabetes (right). With prolonged exposure to moderate metabolic risk (obesity) or severe metabolic risk (diabetes) involving inflammatory activation, production of endothelium-derived vasocontrictors in endothelial cells (blue), intima and subintimal space (orange), and media with its vascular smooth muscle cells (pink/yellow) increases and stimulates to vasoconstriction, cell proliferation and atherosclerotic plaque formation. Part of the figure was adapted from Barton et al., 2007 and reproduced with permission of the publishers. VSMC, vascular smooth muscle cells.

Perspective and implications for therapeutic interventions

It is currently unclear if and how certain drugs, which specifically target obesity and despite drug-related improvements in lipid profile and vascular function, can affect overall morbidity, life expectancy, and quality of life and well-being. One of several unsuccessful recent drug candidates is the cannabinoid antagonist rimonabant, for which clinical trials have been recently terminated due to serious health risks (Kwatra, 2010; Roberfroid et al., 2010; Topol et al., 2010). Whether or not drug therapy can provide the solution to reduce the risk related to obesity (a complex neurophysiological problem with metabolic and physical consequences) remains yet to be shown. However, the underuse of free and readily available, non-pharmacological (i.e. physical) interventions clearly require dramatic behavioural changes to reduce body weight and improve physical fitness and health around the world. Recent studies unfortunately show that the trend towards increases of obesity prevalence continues around the world (Finucane et al., 2011; Heidenreich et al., 2011). Should interventions fail, it appears likely that – for the first time and regardless of all pharmaceutical advances made – mankind could experience a decline in the overall longevity (Olshansky et al., 2005; Stewart et al., 2009) that has increased continously since the beginning of time. Therefore, the preventive power of ‘endothelial therapy’ will hopefully be recognized and put to work where needed.

Acknowledgments

This work was supported by the Swiss National Science Foundation (3200–108258, K33KO-122504 and PBZHP3-135874).

Glossary

COX

cyclooxygenase

EDCF

endothelium-derived contracting factor

EDHF

endothelium-derived hyperpolarizing factor

EDRF

endothelium-derived relaxing factor

ET-1

endothelin-1

ETA

endothelin subtype A receptor

L-NAME

L-nitro arginine methyl ester

LU135252

ETA-selective endothelin antagonist, darusentan

NADPH

nicotineamide adenine dinucleotide phosphate

NO

nitric oxide

O2-

superoxide anion

ONOO-

peroxynitrite

Conflict of Interest

There are no conflicts of interest involved for any of the authors.

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