Tissue factor regulates the crosstalk of coronary perivascular adipose-derived stem cells with vascular cells

Background and Aims: The quantity of coronary perivascular adipose tissue (CPVAT) has been associated to the underlying vessel atherosclerotic plaque severity. The role of the adipose stem cells (ASCs) reservoir in CPVAT on the underlying arterial smooth muscle cells (VSMCs) function is not known. To determinate the interactions between ASCs present on CPVAT obtained from perivascular niche of non-ischemic or ischemic patients with VSMCs presents on the media, which play a central role in atherosclerosis plaque development. Methods: ASCs were obtained from the PVAT overlying the left anterior descending coronary arteries (LAD) of patients undergoing heart transplantation. ASCs were phenotypically characterized, and functionally tested by proliferation, differentiation and angiogenic assays. Co-cultures of ASC and VSMCs were used in vitro and in vivo studies to analyze the effect of ASCs on VSMCs. Results: ASCs expressing typical mesenchymal stem cell markers were detected in the adventitia of the LAD. The differentiation capacity and angiogenic potential of ASCs were evidenced. We identified tissue factor (TF) expressed in ASCs as responsible of ASCs differentiation and recruitment of VSMCs through ERK1/2 /ETS1 signaling. ASCs obtained from non-ischemic or ischemic tissue showed different expression of TF, and consequently different angiogenic capacity. Upregulation of TF in ischemic-ASCs, increased their angiogenic capacity in subcutaneously implanted plugs in mice, whereas silencing TF in ASCs decreased the proangiogenic capacity of non-ischemic ASCs. Conclusions: Our results indicate for the first time a novel mechanism of regulation of vascular function by stem cells of the perivascular fat. CPVAT-ASCs drive angiogenic and proliferative processes in VSMC,mediated by TF expression in ASCs.