Chan Xin Yi, Volkova Eugenia, Eoh Joon, Black Rebecca, Fang Lilly, Gorashi Rayyan, Song Jihyun, Wang Jing, Elliott Morgan B, Barreto-Ortiz Sebastian F, Chen James, Lin Brian L, Santhanam Lakshmi, Cheng Linzhao, Lee Frank S, Prchal Josef T, Gerecht Sharon
Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
Hematology, University of Utah School of Medicine and Huntsman Cancer Center, Salt Lake City, UT 84132, USA.
iScience. 2021 Mar 2;24(4):102246. doi: 10.1016/j.isci.2021.102246. eCollection 2021 Apr 23.
Heterozygous gain-of-function (GOF) mutations of hypoxia-inducible factor 2α (HIF2A), a key hypoxia-sensing regulator, are associated with erythrocytosis, thrombosis, and vascular complications that account for morbidity and mortality of patients. We demonstrated that the vascular pathology of HIF2A GOF mutations is independent of erythrocytosis. We generated HIF2A GOF-induced pluripotent stem cells (iPSCs) and differentiated them into endothelial cells (ECs) and smooth muscle cells (SMCs). Unexpectedly, HIF2A-SMCs, but not HIF2A-ECs, were phenotypically aberrant, more contractile, stiffer, and overexpressed endothelin 1 (EDN1), myosin heavy chain, elastin, and fibrillin. EDN1 inhibition and knockdown of -receptors both reduced HIF2-SMC stiffness. Hif2A GOF heterozygous mice displayed pulmonary hypertension, had SMCs with more disorganized stress fibers and higher stiffness in their pulmonary arterial smooth muscle cells, and had more deformable pulmonary arteries compared with wild-type mice. Our findings suggest that targeting these vascular aberrations could benefit patients with HIF2A GOF and conditions of augmented hypoxia signaling.
缺氧诱导因子2α（HIF2A）是一种关键的缺氧感知调节因子，其杂合功能获得性（GOF）突变与红细胞增多症、血栓形成及血管并发症相关，这些并发症是患者发病和死亡的原因。我们证明，HIF2A GOF突变的血管病变与红细胞增多症无关。我们生成了HIF2A GOF诱导的多能干细胞（iPSC），并将其分化为内皮细胞（EC）和平滑肌细胞（SMC）。出乎意料的是，HIF2A-SMC在表型上出现异常，收缩性更强、更僵硬，且内皮素1（EDN1）、肌球蛋白重链、弹性蛋白和原纤蛋白表达上调，而HIF2A-EC则没有。EDN1抑制和受体敲低均降低了HIF2-SMC的硬度。与野生型小鼠相比，Hif2A GOF杂合小鼠表现出肺动脉高压，其肺动脉平滑肌细胞中的SMC应力纤维更紊乱、硬度更高，且肺动脉更易变形。我们的研究结果表明，针对这些血管异常可能使患有HIF2A GOF和缺氧信号增强病症的患者受益。
