The coronary perivascular adipose tissue (cPVAT) has been associated to the burden of cardiovascular risk factors and to the underlying vessel atherosclerotic plaque severity. Although the “outside to inside” hypothesis of PVAT-derived-adipokine regulation of vessel function is currently accepted, whether the resident mesenchymal stem cells (ASCs) in PVAT have a regulatory role on the underlying vascular arterial smooth muscle cells (VSMCs) is not known. Here, we investigated the interactions between resident PVAT-ASCs and VSMCs. ASCs were obtained from PVAT overlying the left anterior descending (LAD) coronary artery of hearts removed at heart transplant operations. PVAT was obtained both from patients with non-ischemic and ischemic heart disease as the cause of heart transplant. ASCs were isolated from PVAT, phenotypically characterized by flow cytometry, functionally tested for proliferation, and differentiation. Crosstalk between ASCs and VSMCs was investigated by co-culture studies. ASCs were detected in the adventitia of the LAD-PVAT showing differentiation capacity and angiogenic potential. ASCs obtained from PVAT of non-ischemic and ischemic hearts showed different tissue factor (TF) expression levels, different VSMCs recruitment capacity through the axis ERK1/2-ETS1 signaling and different angiogenic potential. Induced upregulation of TF in ASCs isolated from ischemic PVAT rescued their angiogenic capacity in subcutaneously implanted plugs in mice, whereas silencing TF in ASCs decreased the proangiogenic capacity of non-ischemic ASCs. The results indicate for the first time a novel mechanism of regulation of VSMCs by PVAT-ASCs in angiogenesis, mediated by TF expression in ASCs. Regulation of TF in ASCs may become a therapeutic intervention to increase cardiac protection.

冠状动脉血管周围脂肪组织（cPVAT）与心血管危险因素的负担以及潜在血管动脉粥样硬化斑块的严重程度相关。尽管PVAT衍生的脂肪因子调节血管功能的“从外到内”假说目前已被接受，但PVAT中驻留的间充质干细胞（ASC）是否对底层血管动脉平滑肌细胞（VSMC）具有调节作用尚不明确。已知。在这里，我们研究了驻留 PVAT-ASC 和 VSMC 之间的相互作用。 ASCs 是从覆盖心脏移植手术中摘除的心脏左前降支 (LAD) 冠状动脉的 PVAT 中获得的。 PVAT 是从因心脏移植而患有非缺血性和缺血性心脏病的患者中获得的。 ASCs 从 PVAT 中分离出来，通过流式细胞术进行表型表征，并进行增殖和分化功能测试。通过共培养研究调查了 ASC 和 VSMC 之间的串扰。在 LAD-PVAT 外膜中检测到 ASC，显示出分化能力和血管生成潜力。从非缺血性心脏和缺血性心脏的PVAT获得的ASC表现出不同的组织因子（TF）表达水平、通过轴ERK1/2-ETS1信号传导不同的VSMC募集能力以及不同的血管生成潜力。从缺血性PVAT中分离出的ASC中诱导的TF上调可挽救其在小鼠皮下植入的栓塞中的血管生成能力，而沉默ASC中的TF会降低非缺血性ASC的促血管生成能力。该结果首次表明PVAT-ASC在血管生成中调节VSMC的新机制，该机制是由ASC中的TF表达介导的。 ASC 中 TF 的调节可能成为增强心脏保护的治疗干预措施。