Mechanisms of Perivascular Adipose Tissue Dysfunction in Obesity

Most blood vessels are surrounded by adipose tissue. Similarly to the adventitia, perivascular adipose tissue (PVAT) was considered only as a passive structural support for the vasculature, and it was routinely removed for isolated blood vessel studies. In 1991, Soltis and Cassis demonstrated for the first time that PVAT reduced contractions to noradrenaline in rat aorta. Since then, an important number of adipocyte-derived factors with physiological and pathophysiological paracrine vasoactive effects have been identified. PVAT undergoes structural and functional changes in obesity. During early diet-induced obesity, an adaptative overproduction of vasodilator factors occurs in PVAT, probably aimed at protecting vascular function. However, in established obesity, PVAT loses its anticontractile properties by an increase of contractile, oxidative, and inflammatory factors, leading to endothelial dysfunction and vascular disease. The aim of this review is to focus on PVAT dysfunction mechanisms in obesity

Anticontractile Effect of Perivascular Adipose Tissue and Leptin are Reduced in Hypertension

Leptin causes vasodilatation both by endothelium-dependent and -independent mechanisms. Leptin is synthesized by perivascular adipose tissue (PVAT). The hypothesis of this study is that a decrease of leptin production in PVAT of spontaneously hypertensive rats (SHR) might contribute to a diminished paracrine anticontractile effect of the hormone. We have determined in aorta from Wistar-Kyoto (WKY) and SHR (i) leptin mRNA and protein levels in PVAT, (ii) the effect of leptin and PVAT on contractile responses, and (iii) leptin-induced relaxation and nitric oxide (NO) production. Leptin mRNA and protein expression were significantly lower in PVAT from SHR. Concentration-response curves to angiotensin II were significantly blunted in presence of PVAT as well as by exogenous leptin (10−9 M) only in WKY. This anticontractile effect was endothelium-dependent. Vasodilatation induced by leptin was smaller in SHR than in WKY, and was also endothelium-dependent. Moreover, release of endothelial NO in response to acute leptin was higher in WKY compared to SHR, but completely abolished in the absence of endothelium. In conclusion, the reduced anticontractile effect of PVAT in SHR might be attributed to a reduced PVAT-derived leptin and to an abrogated effect of leptin on endothelial NO release probably due to an impaired activation of endothelial NO synthase

Mechanisms of Perivascular Adipose Tissue Dysfunction in Obesity

Most blood vessels are surrounded by adipose tissue. Similarly to the adventitia, perivascular adipose tissue (PVAT) was considered only as a passive structural support for the vasculature, and it was routinely removed for isolated blood vessel studies. In 1991, Soltis and Cassis demonstrated for the first time that PVAT reduced contractions to noradrenaline in rat aorta. Since then, an important number of adipocyte-derived factors with physiological and pathophysiological paracrine vasoactive effects have been identified. PVAT undergoes structural and functional changes in obesity. During early diet-induced obesity, an adaptative overproduction of vasodilator factors occurs in PVAT, probably aimed at protecting vascular function. However, in established obesity, PVAT loses its anticontractile properties by an increase of contractile, oxidative, and inflammatory factors, leading to endothelial dysfunction and vascular disease. The aim of this review is to focus on PVAT dysfunction mechanisms in obesity

E_max and pD₂ values of Ach-induced relaxation in mesenteric arteries (MA-PVAT) and in the perfused mesenteric bed (MB).

<p>MA (Isolated mesenteric arteries), MB (perfused mesenteric bed). E_max, is the maximal relaxation to acetylcholine in % of precontraction to noradrenaline. pD₂, is the negative logarithm of molar concentration of Ach causing half maximal responses. AUC, is the area under concentration-response curves expressed in mmHg for MB and mg for MA. Data are expressed as mean ± S.E.M., n≥5. **p<0.01, ***p<0.001, compared to their corresponding matched control groups. ^#p<0.05, ^###p<0.001 compared to the control group.</p

Effect of PVAT on contractile responses to noradrenaline.

<p>Cumulative concentration-response curves to noradrenaline (NA, 1 nM–10 µM) in MA with (+) and without (−) PVAT from control (C) [A] and high fat diet (HFD) animals [B]. Data are means ± S.E.M. (n≥5 animals per group). **p<0.01, compared to MA (-) PVAT. Cumulative concentration-response curves to NA (0.1–10 µM) in MB from C and HFD animals [C]. Data are means ± S.E.M. (n≥5 animals per group). **p<0.01, compared with C.</p

Contribution of pro-oxidant systems on contractile responses to noradrenaline in both mesenteric arteries and the mesenteric bed.

<p>[A] Confocal projections showing <i>in situ</i> superoxide generation determined with dihydroethidium (DHE, 3 µM) in mesenteric PVAT from control (C) and high fat diet (HFD) animals. [B] NOX activity in mesenteric PVAT. Results are expressed as percentage of NOX activity in C. Data are means ± S.E.M. (n≥5 animals per group). *p<0.05 compared to C animals. [C] Cumulative concentration-response curves to noradrenaline (NA, 0.1–10 µM) in MB and [D] cumulative concentration-response curves to NA (1 nM–10 µM) in MA from C and HFD animals in absence/presence of apocynin (0.1 mM). Data are means ± S.E.M. (n≥5 animals per group). ^#p<0.05; ^###p<0.001 compared to their corresponding matched control groups.</p

Contribution of antioxidant systems on contractile responses to noradrenaline in both mesenteric arteries and the mesenteric bed.

<p>Effect of HFD on ec-SOD protein expression in mesenteric PVAT [A] and in MA [B]. Diagram bars show the result of densitometric analysis of ec-SOD immunoblots, expressed as percentage of ec-SOD in the control (C) group. Data are means ± S.E.M. (n≥5 animals per group). Total SOD activity in mesenteric PVAT [C] and in MA [D]. Data are presented as means ± S.E.M. (n≥5 animals per group). *p<0.05 compared to C animals. [E] Cumulative concentration-response curves to noradrenaline (NA, 0.1–10 µM) in MB and [F] cumulative concentration-response curves to NA (0.1–10 µM) in MA from C and HFD animals in absence/presence of 3-amino-1,2,4-triazole (3-AT, 20 mM). Data are means ± S.E.M. (n≥5 animals per group). ^##p<0.01; ^###p<0.001 compared to their corresponding matched control groups.</p

eNOS phosphorylation and NOX activity in mesenteric arteries.

<p>[A] Representative immunoblots of p-eNOS in MA. Diagram bars show the result of densitometric analysis of p-eNOS immunoblots, expressed as percentage of p-eNOS/eNOS in the control (C) group. Data are means ± S.E.M. (n≥5 animals per group). *p<0.05 compared to C. [B] NOX activity in MA. Results are expressed as percentage of NADPH oxidase activity in C animals. Data are means ± S.E.M. (n≥5 animals per group). *p<0.05 compared to C.</p