Perivascular Adipose Tissue–Derived Complement 3 Is Required for Adventitial Fibroblast Functions and Adventitial Remodeling in Deoxycorticosterone Acetate–Salt Hypertensive Rats

Abstract

Objective-To examine the role of perivascular adipose tissue (PVAT)-derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo. Methods and Results-PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by ␣-smooth muscle-actin induction. We identified the secretome of PVAT by liquid chromatography-tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium-induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in deoxycorticosterone acetate-salt hypertensive rats. Key Words: perivascular adipose tissue Ⅲ migration Ⅲ ␣-smooth muscle actin Ⅲ complement 3 Ⅲ hypertensive rats Ⅲ adventitial fibroblasts A lmost all blood vessels are surrounded by perivascular adipose tissue (PVAT), which has been considered merely a structural support for vasculature. Recent studies revealed that PVAT produced and released various bioactive substances, playing a dual role in the regulation of vascular function. 1 Adipocyte-derived relaxing factors released from PVAT have attenuated the contractile response of rat aorta responding to norepinephrine. 2,3 However, PVAT also promoted vasoconstriction through production of superoxide and inflammatory cytokines, such as tumor necrosis factor ␣ (TNF␣) and interleukin 6. 4,5 In particular, the conditioned medium of PVAT induced vascular smooth muscle cell (VSMC) proliferation through activation of mitogen-activated protein kinase (MAPK) pathways via paracrine adipokines. 6,7 In pathophysiologic processes of vascular remodeling, phenotypic changes in perivascular cells correlated with upregulation of proinflammatory adipocytokines, which may contribute to vascular dysfunction. 8,9 The list of bioactive factors released from PVAT is increasing, and the role of these adipocytokines in the regulation of vascular function is being unraveled. 10,11 Multiple lines of evidence suggest that vascular adventitial fibroblasts (AFs), the major cell component of adventitia, play a vital role in regulating the structure and function of blood vessels. 12,13 Previous studies 14,15 indicated that numerous active cytokines induce AF migration, which may be associated with the pathogenesis of neointimal formation. Although AFs are in closer proximity to PVAT compared with VSMCs, little attention has been devoted to the role of PVAT-der...

Two Sides of MGP Null Arterial Disease

“…Thus, adipsin (also known as complement factor D) cleaves factor B (46 -48), potentially connecting adipose and complement activation. Accumulating evidence on the involvement of this protease in vascular pathology adds to the complex effects of complement on vasculature, exemplified by the ability of complement proteins C3 and C4 to increase vascular stiffness in atherosclerosis through binding to collagen and elastin (49) and to stimulate adventitial fibroblast migration and differentiation in a rat model of hypertension (50).…”

Pericoronary Adipose Tissue as Possible Supply Site and Storage for Lipoproteins in Human Coronary Artery

“…Perivascular adipocytes (PVA) deliver substantial quantities of metabolically dynamic substances with both endocrine and paracrine actions [19]; PVA of human internal thoracic artery release NO [20]; PVA discharges nicotinamide adenine dinucleotide phosphateoxidase in mice [21]; rat PVA discharge compliment [23,22]; rat PVA discharge metylpalmitate ester [23]; different substances, for example, plasminogen activator inhibitor-1 and interleukin-6 are contained in epicardial adipose tissue in patients with acute coronary syndrome [24]; cultured human epicardial adipose tissues release glutation S-transferase P and ApoA1 [25]. But, reports depicting release and storage of lipoproteins from human PVA, including PCAT, to the nearby vessel wall were not found.…”

Perivascular adipose tissue: role in the pathogenesis of obesity, type 2 diabetes mellitus and cardiovascular pathology.

“…Показано, что у данных видов грызунов коронарные артерии и грудной отдел аорты окружены бурыми адипоцитами, жировая ткань под-вздошно-бедренных артерий содержит в равной сте-пени бурые и белые клетки, тогда как периваскулярная жировая ткань абдоминальной аорты и мезентери-альных артерий состоит из белых адипоцитов [7,9]. Остается открытым вопрос о характере периваску-лярной жировой ткани коронарных артерий: имеются данные о том, что правая венечная артерия окружена адипоцитами с высоким уровнем экспрессии генов бурой жировой ткани, для других коронарных артерий характерны маркеры белой жировой ткани [10,11].…”

“…Проведено сравнение свойств сосудов грызунов с бурой периваскулярной жировой тканью и сосудов грызунов без рецептора, активируемого про-лифератором пероксисом на клетках гладкомышеч-DOI: 10.14341/OMET201545-13 Ожирение и метаболизм. 2015;12(4): [5][6][7][8][9][10][11][12][13] О б з о р ы л и т е р а т у р ы ного слоя (SMPG-нокаутные мыши). Нокаутирование гена рецептора вызывает полное отсутствие у живот-ных периваскулярной жировой ткани.…”