Rab27a Regulates Human Perivascular Adipose Progenitor Cell Differentiation.

Abstract

Perivascular adipose tissue (PVAT) surrounds blood vessels and regulates vascular tone through paracrine secretion of cytokines. During conditions promoting cardiometabolic dysfunction, such as obesity, cytokine secretion is altered towards a proinflammatory and proatherogenic profile. Despite the clinical implications for cardiovascular disease, studies addressing the biology of human PVAT remain limited. We are interested in characterizing the resident adipose progenitor cells (APCs) because of their potential role in PVAT expansion during obesity. We also focused on proteins regulating paracrine interactions, including the small GTPase Rab27a, which regulates protein trafficking and secretion. PVAT from the ascending aorta was collected from patients with severe cardiovascular disease undergoing coronary artery bypass grafting (CABG). Freshly-isolated PVAT was digested and APC expanded in culture for characterizing progenitor markers, evaluating adipogenic potential and assessing the function(s) of Rab27a. Using flow cytometry, RT-PCR, and immunoblot, we characterized APC from human PVAT as negative for CD45 and CD31 and expressing CD73, CD105, and CD140A. These APCs differentiate into multilocular, UCP1-producing adipocytes in vitro. Rab27a was detected in interstitial cells of human PVAT in vivo and along F-actin tracks of PVAT-APC in vitro. Knockdown of Rab27a using siRNA in PVAT-APC prior to induction resulted in a marked reduction in lipid accumulation and reduced expression of adipogenic differentiation markers. PVAT-APC from CABG donors express common adipocyte progenitor markers and differentiate into UCP1-containing adipocytes. Rab27a has an endogenous role in promoting the maturation of adipocytes from human PVAT-derived APC.