Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2α.
Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2α.
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DOI：
10.1161/circulationaha.116.021494
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发表时间：
2016-06-14
期刊：
影响因子：
37.8
通讯作者：
Zhao YY
中科院分区：
文献类型：
--
作者：
Dai Z;Li M;Wharton J;Zhu MM;Zhao YY
血管闭塞和复杂的丛状病变是严重肺动脉高压（PAH）患者的病理特征。然而，闭塞性血管重构的机制仍然难以捉摸，因此目前的治疗方法并没有针对基本的疾病改变机制，只导致发病率和死亡率的适度改善。在内皮细胞（ECs）和造血细胞中，tie2cre介导的Egln1（编码脯氨酸-4羟化酶2，PHD2） （Egln1Tie2）被破坏的小鼠表现出自发性严重的PAH，并伴有广泛的肺血管重构，包括血管闭塞和类似临床PAH病理特征的丛状样病变。在特发性PAH患者中，Egln1Tie2小鼠表现出前所未有的右心室肥厚、衰竭和进行性死亡。与此一致的是，PHD2在特发性PAH患者肺血管闭塞的肺内皮细胞中表达减少。Egln1和Hif1a或Egln1和Hif2a的基因缺失表明，缺氧诱导因子-2α (HIF-2α)是Egln1Tie2小鼠中严重PAH的关键介质。我们还观察到Egln1Tie2肺中许多ph引起基因的表达改变，这些基因在Egln1Tie2/Hif2aTie2肺中也正常表达。phd2缺失的ECs部分通过hif -2α激活的CXCL12表达促进平滑肌细胞增殖。基因缺失excl12可减弱Egln1Tie2小鼠的PAH。这些研究确定了PHD2缺乏在严重PAH机制中的意想不到的作用，并确定了第一个具有闭塞性血管重构和病理生理重现临床PAH的转基因小鼠模型。因此，靶向PHD2/HIF-2α信号是逆转血管重构治疗严重PAH的一种有希望的策略。
Vascular occlusion and complex plexiform lesions are hallmarks of the pathology of severe pulmonary arterial hypertension (PAH) in patients. However, mechanisms of obliterative vascular remodeling remain elusive and hence current therapies have not targeted the fundamental disease modifying mechanisms and result in only modest improvement in morbidity and mortality. Mice with Tie2Cre-mediated disruption of Egln1 (encoding prolyl-4 hydroxylase 2, PHD2) (Egln1Tie2) in endothelial cells (ECs) and hematopoietic cells exhibited spontaneous severe PAH with extensive pulmonary vascular remodeling including vascular occlusion and plexiform-like lesions resembling the hallmarks of the pathology of clinical PAH. As seen in idiopathic PAH patients, Egln1Tie2 mice exhibited unprecedented right ventricular hypertrophy and failure and progressive mortality. Consistently, PHD2 expression was diminished in lung ECs of obliterated pulmonary vessels in idiopathic PAH patients. Genetic deletions of both Egln1 and Hif1a or Egln1 and Hif2a identified hypoxia-inducible factor-2α (HIF-2α) as the critical mediator of severe PAH seen in Egln1Tie2 mice. We also observed altered expression of many PH-causing genes in Egln1Tie2 lungs which was also normalized in Egln1Tie2/Hif2aTie2 lungs. PHD2-deficient ECs promoted smooth muscle cell proliferation in part through HIF-2α-activated CXCL12 expression. Genetic deletion of Cxcl12 attenuated PAH in Egln1Tie2 mice. These studies defined an unexpected role of PHD2 deficiency in the mechanisms of severe PAH and identified the first genetically modified mouse model with obliterative vascular remodeling and pathophysiology recapitulating clinical PAH. Thus, targeting PHD2/HIF-2α signaling is a promising strategy to reverse vascular remodeling for treatment of severe PAH.