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

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.

Figure 1

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

Effect of 30 weeks of diet-induced obesity in placebo-treated () or endothelin ET_A-receptor antagonist-treated () 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 (), 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 ET_A receptor antagonist darusentan (LU135252) () – 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 (), an effect again completely abrogated after chronic endothelin receptor antagonist treatment which had no effect on obesity (). *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.

Figure 3

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 ET_A receptor; total ERK1/2 protein was used as loading control. Diet-induced obesity substantially increases aortic endothelin ET_A 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.

Figure 4

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.