胚胎期冠状血管发育起源及其分子调控机制

Coronary artery disease causes myocardial infarction and heart failure, making it the leading cause of death worldwide. The embryonic origins and developmental mechanisms of coronary vessels remain unclear. The origin of coronary endothelium has ignited controversies during the past two decades and remains an enigma. The proepicardium, sinus venosus, and ventricular endocardium were considered as potential sources of coronary. To address the coronary origin, we have generated inducible endocardium specific Npr3-CreER and sinus venosus endothelial cells specific APJ-CreER knock-in mice. By lineage tracing of endocardium and sinus venosus endothelial cells, we could observe the contribution of them to coronary vessels and provide direct evidence for sinus venosus is the main origin of coronary. We could explore the regulation of VEGF-VEGFR2 signalling during coronary development after endocardial and sinus venosus endothelial knockout of Vegfr2. The present study would not only help us to better understand the origin and developmental program of coronary vessel, but also provide new insight for the field of cardiovascular regenerative medicine.

冠状动脉疾病引起心肌梗死和心衰，是人类因疾病死亡的首要原因。而冠状血管的胚胎起源和发育机制尚未全面了解。在过去的二十年间，冠状血管内皮的起源问题引起了激烈的争论，仍然是未解之谜。目前认为前体心外膜、静脉窦和心室心内膜是冠状血管内皮潜在的细胞起源。为了解析胚胎期冠状血管的起源问题，我们构建了可诱导的心内膜细胞特异性Npr3-CreER和静脉窦内皮细胞特异性APJ-CreER基因敲入小鼠。我们将通过对心内膜和静脉窦内皮细胞进行遗传标记谱系示踪，观察心内膜和静脉窦内皮细胞参与冠状血管形成的情况，为静脉窦是胚胎期冠状血管内皮的主要来源提供直接的证据。通过敲除心内膜和静脉窦内皮细胞中的Vegfr2基因，探索VEGF-VEGFR2信号通路对冠状血管发育过程的调控作用。本项研究将有助于我们更好地了解冠状血管的起源和发育过程，为心血管再生医学领域提供新的思路。

冠状动脉疾病引起心肌梗死和心衰，是人类因疾病死亡的首要原因。而冠状血管的胚胎起 源和发育机制尚未全面了解。在过去的二十年间，冠状血管内皮的起源问题引起了激烈的争论，仍然是未解之谜。目前认为前体心外膜、静脉窦和心室心内膜是冠状血管内皮潜在的细胞起源。为了解析胚胎期冠状血管的起源问题，我们构建了标记心内膜的Nfatc1-Cre和Nfatc1-Dre示踪小鼠，发现Nfatc1不仅标记心内膜也标记很大一部分静脉窦内皮细胞。利用单细胞基因表达分析，我们鉴定出一个新的心内膜标记分子——Npr3，特异性标记心内膜而不标记静脉窦。利用Npr3-CreER小鼠对心内膜细胞进行谱系示踪，结果表明心内膜很少参与胚胎心脏游离心室壁中冠状血管的形成。通过遗传谱系示踪正交实验进一步验证了该研究结果。静脉窦是胚胎期游离心室壁冠状血管内皮的主要来源。这项工作解析了近年来关于冠状血管内皮发育起源的争议，为研究冠状动脉形成和损伤后再生奠定了理论基础。