Lineage Tracing Reveals the Dynamic Contribution of Pericytes to the Blood Vessel Remodeling in Pulmonary Hypertension
Lineage Tracing Reveals the Dynamic Contribution of Pericytes to the Blood Vessel Remodeling in Pulmonary Hypertension
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DOI：
10.1161/atvbaha.119.313715
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发表时间：
2020-03-01
影响因子：
8.7
通讯作者：
Guignabert, Christophe
中科院分区：
文献类型：
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作者：
Bordenave, Jennifer;Tu, Ly;Guignabert, Christophe
目的：肺动脉高压（PAH）时肺血管壁驻留细胞的过度聚集是肺血管重构的标志性特征。此外，我们以前已经证明，肺动脉高压中的肺小动脉被周细胞过度覆盖，但这一过程尚未完全理解。我们的研究的目的是探讨周细胞在PAH血管remodeling.Approach和结果的动态贡献：在这项研究中，我们进行了原位，在体内和体外实验。我们从对照组和PAH肺标本中分离人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）。此外，为了跟踪周细胞数量和命运，在慢性缺氧期间发生的肺小动脉肌化模型中，使用NG 2CreER;mT/mG转基因小鼠的遗传命运作图方法。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（C-X-C基序趋化因子受体）-7和TGF（转化生长因子）-β RII，从而显示出比对照组更高的迁移、增殖和分化为平滑肌样细胞的能力。在慢性缺氧的体内模型中，我们发现CXCL中周细胞数量的早期增加，（C-X-C基序趋化因子配体）-12依赖的方式，而稍后，从第7天起，典型TGF-β信号传导通路的激活诱导周细胞分化为平滑肌样细胞。我们的研究结果揭示了肺周细胞在PAH中的关键作用，并鉴定了CXCR-7和TGF-β 1。β RII作为这些驻留祖血管细胞中的2种内在异常，促进肺血管中PAH结构变化的发生和维持。
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)-beta RII 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-beta 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-beta RII as 2 intrinsic abnormalities in these resident progenitor vascular cells that foster the onset and maintenance of PAH structural changes in blood lung vessels.