Increased caveolae density and caveolin-1 expression accompany impaired NO-mediated vasorelaxation in diet-induced obesity

Abstract

Diet-induced obesity induces changes in mechanisms that are essential for the regulation of normal artery function, and in particular the function of the vascular endothelium. Using a rodent model that reflects the characteristics of human dietary obesity, in the rat saphenous artery we have previously demonstrated that endothelium-dependent vasodilation shifts from an entirely nitric oxide (NO)-mediated mechanism to one involving upregulation of myoendothelial gap junctions and intermediate conductance calcium-activated potassium channel activity and expression. This study investigates the changes in NO-mediated mechanisms that accompany this shift. In saphenous arteries from controls fed a normal chow diet, acetylcholine-mediated endothelium-dependent vasodilation was blocked by NO synthase and soluble guanylyl cyclase inhibitors, but in equivalent arteries from obese animals sensitivity to these agents was reduced. The expression of endothelial NO synthase (eNOS) and caveolin-3 in rat saphenous arteries was unaffected by obesity, whilst that of caveolin-1 monomer and large oligomeric complexes of caveolins-1 and -2 were increased in membrane-enriched samples. The density of caveolae was increased at the membrane and cytoplasm of endothelial and smooth muscle cells of saphenous arteries from obese rats. Dissociation of eNOS from caveolin-1, as a prerequisite for activation of the enzyme, may be compromised and thereby impair NO-mediated vasodilation in the saphenous artery from diet-induced obese rats. Such altered signaling mechanisms in obesity-related vascular disease represent significant potential targets for therapeutic intervention.

Endothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase

“…By contrast, cav-3 is the only isoform expressed in cardiomyocytes, visceral-smooth muscle and skeletal muscle cells. 4, 5 These specialized regions act to reduce the fluidity of the plasma membranes that they segregate. 6 Using transmission electron microscopy, we show in Figure 1 the overall shape and location of caveolae in ovine uterine artery endothelial cells (UAECs) and are identified by the arrows.…”

“…Studies that utilized an over-expression of cav-1 have showed a reduced basal NO production in a “control” cellular state, cav-1 interaction with eNOS has been shown to negatively regulate NO release. 4 It has been established that eNOS requires palmitoylation and myristoylation in order to be targeted to the caveolae microdomains. Upon agonist activation, (e.g.…”

Interactive effects of in vitro binge-like alcohol and ATP on umbilical endothelial nitric oxide synthase post-translational modifications and redox modulation

“…Interestingly, control endothelial cells were not programmed for altered protein expression upon ATP treatment. Over-expression of cav-1 leads to decreased NO production and cav-1 interaction with eNOS negatively regulates basal NO release [33]. Thus, eNOS and cav-1 are significant targets of chronic alcohol exposure [34-36] in the umbilical vascular endothelial cells.…”

New insights into the role of soluble guanylate cyclase in blood pressure regulation

“…In the microcirculation (cremaster muscle arterioles) of diet-induced obese rats, endothelial caveolae density is decreased, which leads to improved NOS3 function and sGC-dependent vasodilation [17]. In contrast, in saphenous arteries from obese rats, increased endothelial caveolae density and caveolin-1 expression levels are associated with inhibition of NOS3 activity and impaired vasorelaxation [18]. These seemingly conflicting results most likely reflect vascular bed-specific modulation of caveolins in response to obesity.…”