Pericytes differentiate into smooth muscle cells through HIF2a/SDF1 activation

摘要 肺动脉高压（PAH）是一种以肺压升高为特征的危及生命的疾病， 右心衰竭和过早死亡目前的治疗由于不能预防疾病进展， 抑制和/或逆转肺动脉平滑肌细胞（PASMC）驱动的远端肌化 微血管这些高度增殖的PASMCs的起源仍不完全清楚，但可能是 与邻近周细胞（PC）群体的适应不良行为密切相关。除了提供 作为毛细血管的壁支持，PC可以在应激反应中分化成其他细胞类型。我们最近报道 人类PAH肺PC与PASMC具有相同的谱系标记和功能特性，如形态学 和收缩性。因此，我们假设PAH血管病变中的PASMCs起源于毛细血管PC。 慢性缺氧小鼠PC的命运图显示，PC从毛细血管中解离，并重新定位到 毛细血管前小动脉，在那里它们共同表达成熟SMC的标志物并有助于肌化。 通过单细胞和批量RNA-seq分析，我们发现HIF 2A/SDF 1信号通路是一个重要的信号通路。 是PC分化为SMC的主要调节剂，也是PAH中PC功能障碍的主要调节剂。我们 建议：1）证明HIF 2a/SDF 1激活导致PC从肺毛细血管解离，2） 定义了HIF 2a/SDF 1信号转导驱动PC分化为PASMC样细胞的分子机制， 人和小鼠，以及3）确定在PC中操纵HIF 2a/SDF 1是否可以改变血管损伤的严重性。 该项目将提供新的见解周细胞病理生物学和建立 HIF 2a/SDF 1作为PAH的潜在治疗靶点，其第一种逆转肌化的药物， 可以发现PAH中改善结果。

ABSTRACT Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated lung pressures, right heart failure, and premature death. Current therapies fail to prevent disease progression due to their inability to suppress and/or reverse pulmonary arterial smooth muscle cells (PASMCs) driven muscularization of distal microvessels. The origin of these highly proliferative PASMCs remains incompletely understood, but may be closely related to the maladaptive behavior of contiguous pericyte (PC) populations. In addition to providing mural support to capillaries, PCs can differentiate into other cell types in response to stress. We recently reported that human PAH lung PCs share lineage markers and functional properties with PASMCs, such as morphology and contractility. We thus hypothesize that PASMCs in PAH vascular lesions originate from capillary PCs. Fate-mapping of PCs in chronic hypoxia mice revealed that PCs dissociate from capillaries and relocate to precapillary arterioles, where they co-express markers of mature SMCs and contribute to muscularization. Through single cell and bulk RNA-seq analysis, we discovered that the HIF2A/SDF1 signaling pathway is a master regulator of differentiation of PCs into SMC and a major modifier of PC dysfunction in PAH. We propose to: 1) demonstrate that HIF2a/SDF1 activation causes PC dissociation from pulmonary capillaries, 2) define the molecular mechanism by which HIF2a/SDF1 signaling drives PC differentiation into PASMC-like in human and mice, and 3) determine whether manipulation of HIF2a/SDF1 in PCs can alter the severity of vascular remodeling in animal models of PH. This project will provide novel insight into pericyte pathobiology and establish HIF2a/SDF1 as a potential therapeutic target in PAH, for which the first drugs to reverse muscularization and improve outcomes in PAH may be found.