OBJECTIVE Excessive accumulation of resident cells within the pulmonary vascular wall represents the hallmark feature of the remodeling occurring in pulmonary arterial hypertension (PAH). Furthermore, we have previously demonstrated that pulmonary arterioles are excessively covered by pericytes in PAH, but this process is not fully understood. The aim of our study was to investigate the dynamic contribution of pericytes in PAH vascular remodeling. Approach and Results: In this study, we performed in situ, in vivo, and in vitro experiments. We isolated primary cultures of human pericytes from controls and PAH lung specimens then performed functional studies (cell migration, proliferation, and differentiation). In addition, to follow up pericyte number and fate, a genetic fate-mapping approach was used with an NG2CreER;mT/mG transgenic mice in a model of pulmonary arteriole muscularization occurring during chronic hypoxia. We identified phenotypic and functional abnormalities of PAH pericytes in vitro, as they overexpress CXCR (C-X-C motif chemokine receptor)-7 and TGF (transforming growth factor)-βRII and, thereby, display a higher capacity to migrate, proliferate, and differentiate into smooth muscle-like cells than controls. In an in vivo model of chronic hypoxia, we found an early increase in pericyte number in a CXCL (C-X-C motif chemokine ligand)-12-dependent manner whereas later, from day 7, activation of the canonical TGF-β signaling pathway induces pericytes to differentiate into smooth muscle-like cells. CONCLUSIONS Our findings reveal a pivotal role of pulmonary pericytes in PAH and identify CXCR-7 and TGF-βRII as 2 intrinsic abnormalities in these resident progenitor vascular cells that foster the onset and maintenance of PAH structural changes in blood lung vessels.

中文翻译：

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谱系追踪揭示了肺动脉高压中周细胞对血管重构的动态贡献。

目的肺血管壁内驻留细胞的过度积累代表着肺动脉高压（PAH）中发生的重塑的标志性特征。此外，我们以前已经证明，肺动脉小动脉被PAH中的周细胞过度覆盖，但是此过程尚未完全了解。我们研究的目的是研究周细胞在PAH血管重塑中的动态作用。方法和结果：在这项研究中，我们进行了原位，体内和体外实验。我们从对照和PAH肺标本中分离出人类周细胞的原代培养物，然后进行功能研究（细胞迁移，增殖和分化）。另外，为了追踪周细胞数量和命运，NG2CreER使用了遗传命运映射方法。mT / mG转基因小鼠在慢性低氧期间发生的肺小动脉肌肉化模型中。我们在体外鉴定了PAH周细胞的表型和功能异常，因为它们过表达CXCR（CXC基序趋化因子受体）-7和TGF（转化生长因子）-βRII，从而表现出更高的迁移，增殖和分化成平滑细胞的能力。肌肉样细胞比对照组。在慢性缺氧的体内模型中，我们发现CXCL（CXC基序趋化因子配体）-12依赖性方式的周细胞数早期增加，而后来，从第7天起，经典TGF-β信号通路的激活诱导周细胞向分化成平滑肌样细胞。