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和潜在的血管动脉粥样硬化斑块的严重程度有关。尽管目前接受了 PVAT 衍生的脂肪因子调节血管功能的“由外到内”假说，但 PVAT 中的常驻间充质干细胞 （ASC） 是否对下面的血管动脉平滑肌细胞 （VSMC） 具有调节作用尚不清楚。在这里，我们研究了常驻 PVAT-ASC 和 VSMC 之间的相互作用。ASC 是从心脏移植手术中切除的心脏左前降支 （LAD） 冠状动脉上的 PVAT 获得的。PVAT 是从非缺血性和缺血性心脏病患者那里获得的，是心脏移植的原因。ASCs 是从 PVAT 中分离出来的，通过流式细胞术进行表型特征，对增殖和分化进行功能测试。通过共培养研究调查 ASCs 和 VSMCs 之间的串扰。在 LAD-PVAT 外膜中检测到 ASCs，显示出分化能力和血管生成潜力。从非缺血性和缺血性心脏的 PVAT 获得的 ASCs 表现出不同的组织因子 （TF） 表达水平、不同的 VSMCs 通过轴 ERK1/2-ETS1 信号传导的募集能力和不同的血管生成电位。从缺血性 PVAT 分离的 ASCs 中诱导 TF 的上调挽救了它们在小鼠皮下植入的栓子中的血管生成能力，而沉默 ASCs 中的 TF 降低了非缺血性 ASCs 的促血管生成能力。结果首次表明 PVAT-ASCs 在血管生成中调节 VSMC 的新机制，由 ASCs 中的 TF 表达介导。 在 ASC 中调节 TF 可能成为一种增加心脏保护的治疗干预措施。