Cardiovascular-Program, Institut de Recerca Sant Pau, IIB-Sant Pau, Carrer Sant Quintí, 77-79, 08041, Barcelona, Spain.
Ciber CV, Instituto Carlos III, Madrid, Spain.
Basic Res Cardiol. 2024 Apr;119(2):291-307. doi: 10.1007/s00395-024-01037-1. Epub 2024 Mar 2.
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）与心血管危险因素负担及潜在血管动脉粥样硬化斑块严重程度有关。尽管目前接受了 PVAT 衍生脂肪因子调节血管功能的“从外到内”假说，但驻留在 PVAT 中的间充质干细胞（ASCs）是否对潜在的血管动脉平滑肌细胞（VSMCs）具有调节作用尚不清楚。在这里，我们研究了驻留的 PVAT-ASCs 和 VSMCs 之间的相互作用。ASCs 是从心脏移植手术中取出的左前降支（LAD）冠状动脉上方的 PVAT 中获得的。PVAT 是从非缺血性和缺血性心脏病患者中获得的，这些患者是心脏移植的原因。从 PVAT 中分离出 ASCs，通过流式细胞术进行表型鉴定，通过增殖和分化功能测试进行功能测试。通过共培养研究研究了 ASCs 和 VSMCs 之间的串扰。在 LAD-PVAT 的外膜中检测到 ASCs，具有分化能力和血管生成潜力。从非缺血性和缺血性心脏的 PVAT 中获得的 ASCs 显示出不同的组织因子（TF）表达水平，通过 ERK1/2-ETS1 信号轴招募不同的 VSMCs 的能力，以及不同的血管生成潜力。在缺血性 PVAT 中分离出的 ASCs 中诱导 TF 的上调挽救了它们在小鼠皮下植入塞子中的血管生成能力，而在非缺血性 ASCs 中沉默 TF 则降低了其促血管生成能力。结果首次表明，在血管生成中，PVAT-ASCs 通过 TF 表达调节 VSMCs 的新机制。ASCs 中 TF 的调节可能成为增加心脏保护的治疗干预措施。
