Selective inactivation of PTEN in smooth muscle cells synergizes with hypoxia to induce severe pulmonary hypertension.
Selective inactivation of PTEN in smooth muscle cells synergizes with hypoxia to induce severe pulmonary hypertension.
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DOI：
10.1161/jaha.113.000188
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发表时间：
2013-05-31
影响因子：
5.4
通讯作者：
Weiser-Evans MC
中科院分区：
文献类型：
--
作者：
Horita H;Furgeson SB;Ostriker A;Olszewski KA;Sullivan T;Villegas LR;Levine M;Parr JE;Cool CD;Nemenoff RA;Weiser-Evans MC
肺动脉高压（PH）的肺血管重构的特征是血管平滑肌细胞（SMC）和外膜成纤维细胞增殖增加、小血管闭塞和炎症细胞积聚。驱动进展的潜在分子机制仍然不明确。我们关注的是SMCs中磷酸酶PTEN的缺失是病理性血管重构的主要驱动因素。我们的目标是通过诱导SMCs中PTEN缺失的小鼠模型来确定PTEN在人类PH和缺氧诱导PH中的作用。人体活检染色显示，与对照组相比，高血压患者的介质中选择性地增强了非活性PTEN。在SMCs中诱导PTEN缺失的小鼠暴露于常氧或缺氧中长达4周。在正常缺氧条件下，SMC PTEN耗竭足以诱导PH特征，与暴露于慢性缺氧的野生型小鼠相似。在缺氧条件下，PTEN的消耗促进了PH的不可逆进展，其特征是压力升高、广泛的肺血管重塑、复杂血管病变的形成、巨噬细胞积累增加，这与促炎细胞因子的协同增加和SMCs和非SMCs的增殖有关。SMC中选择性PTEN的慢性失活是PH进展的关键介质，导致细胞自主事件和与外膜细胞和炎症细胞增殖和募集相关的因子的产生增加，导致疾病的不可逆转进展。
Pulmonary vascular remodeling in pulmonary hypertension (PH) is characterized by increased vascular smooth muscle cell (SMC) and adventitial fibroblast proliferation, small vessel occlusion, and inflammatory cell accumulation. The underlying molecular mechanisms driving progression remain poorly defined. We have focused on loss of the phosphatase PTEN in SMCs as a major driver of pathological vascular remodeling. Our goal was to define the role of PTEN in human PH and in hypoxia‐induced PH using a mouse model with inducible deletion of PTEN in SMCs. Staining of human biopsies demonstrated enhanced inactive PTEN selectively in the media from hypertensive patients compared to controls. Mice with induced deletion of PTEN in SMCs were exposed to normoxia or hypoxia for up to 4 weeks. Under normoxia, SMC PTEN depletion was sufficient to induce features of PH similar to those observed in wild‐type mice exposed to chronic hypoxia. Under hypoxia, PTEN depletion promoted an irreversible progression of PH characterized by increased pressure, extensive pulmonary vascular remodeling, formation of complex vascular lesions, and increased macrophage accumulation associated with synergistic increases in proinflammatory cytokines and proliferation of both SMCs and nonSMCs. Chronic inactivation of PTEN selectively in SMC represents a critical mediator of PH progression, leading to cell autonomous events and increased production of factors correlated to proliferation and recruitment of adventitial and inflammatory cells, resulting in irreversible progression of the disease.