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标题：HIF2A gain-of-function mutation modulates the stiffness of smooth muscle cells and compromises vascular mechanics
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作者：Xin Yi Chan ; Eugenia Volkova ; Joon Eoh 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：4
页码：1-36
DOI：10.1016/j.isci.2021.102246
语种：English
出版社：Elsevier
摘要：SummaryHeterozygous 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 ofEDN1-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.Graphical abstractDisplay OmittedHighlights•HIF2-SMCs are stiffer than WT-SMCs and differ in contractile SMC marker expression•HIF2-SMCs and WT-SMCs differ inEDN1production and ECM composition•HIF- 2α inducesEDN1; EDNI subsequently induces SMC stiffening•Hif2A GOF mouse arterial SMCs have more disorganized stress fibers and are stifferPathophysiology; Biophysics; Biomechanics