Protective Role of Perivascular Adipose Tissue in Endothelial Dysfunction and Insulin-Induced Vasodilatation of Hypercholesterolemic LDL Receptor-Deficient Mice

Abstract

Background: Endothelial dysfunction plays a pivotal role in the initiation of atherosclerosis. Vascular insulin resistance might contribute to a reduction in endothelial nitric oxide (NO) production, leading to impaired endothelium-dependent relaxation in cardiometabolic diseases. Because perivascular adipose tissue (PVAT) controls endothelial function and NO bioavailability, we hypothesized a role for this fat deposit in the vascular complications associated with the initial stages of atherosclerosis. Therefore, we investigated the potential involvement of PVAT in the early endothelial dysfunction in hypercholesterolemic LDL receptor knockout mice (LDLr-KO).Methods: Thoracic aortas with and without PVAT were isolated from 4-month-old C57BL/6J (WT) and LDLr-KO mice. The contribution of PVAT to relaxation responses to acetylcholine, insulin, and sodium nitroprusside was investigated. Western blotting was used to examine endothelial NO synthase (eNOS) and adiponectin expression, as well the insulin signaling pathway in aortic PVAT.Results: PVAT-free aortas of LDLr-KO mice exhibited impaired acetylcholine- and insulin-induced relaxation compared with those of WT mice. Both vasodilatory responses were restored by the presence of PVAT in LDLr-KO mice, associated with enhanced acetylcholine-induced NO levels. PVAT did not change vasodilatory responses to acetylcholine and insulin in WT mice, while vascular relaxation evoked by the NO donor sodium nitroprusside was not modified by either genotype or PVAT. The expression of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), AKT, ERK1/2, phosphorylation of AKT (Ser473) and ERK1/2 (Thr202/Tyr204), and adiponectin was similar in the PVAT of WT and LDLr-KO mice, suggesting no changes in PVAT insulin signaling. However, eNOS expression was enhanced in the PVAT of LDLr-KO mice, while eNOS expression was less abundant in PVAT-free aortas.Conclusion: These results suggest that elevated eNOS-derived NO production in aortic PVAT might be a compensatory mechanism for the endothelial dysfunction and impaired vasodilator action of insulin in hypercholesterolemic LDLr-deficient mice. This protective effect may limit the progression of atherosclerosis in genetic hypercholesterolemia in the absence of an atherogenic diet.

Perivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword

“…Quesada et al demonstrated that PVAT‐derived inflammatory mediators may adversely influence atherosclerotic plaque formation and stability [ 52 ]. Interestingly, PVAT also has been shown a protective role in endothelial dysfunction hypercholesterolemic LDL receptor deficient mice, suggesting that PVAT-derived factors might be involved in the regulation of endothelial function [ 53 ]. Thus, PVAT might actively influence atherosclerosis development in an “outside to inside” manner.…”

Perivascular adipose tissue in cardiovascular diseases – an update

“…Pro-inflammatory substances released by PVAT exhibit a pro-atherogenic role, facilitating the atheromatous plaque stability, being counterbalanced by their protective role in endothelial dysfunction (29). Moreover, as a consequence of its thermogenic effect, tPVAT physiologically contributes to the reduction of the concentration of plasma lipids from vasculature, while aPVAT participates in free fatty acids uptake from circulatory flow, both of which represent anti-atherogenic mechanisms (6).…”

Inflammatory cells in perivascular adipose tissue and the integrity of the tunica media in atherosclerotic coronary arteries

“…For decades, the tunica intima and, partly, the tunica media were the focus of research, and perivascular adipose tissue (PVAT) that surrounds coronary arteries (CAs) was considered to be passive and only supportive tissue. Now, it has become evident that PVAT has a crucial role in maintaining the normal function of CAs [4][5][6], and that it is also involved in the development of CAD [7,8] and hypertension [9]. It has been shown that both vascular smooth muscle and PVAT release a variety of vasoactive factors as well as pro and antiinflammatory cytokines that modulate vascular function and structure [8,[10][11][12][13][14].…”