Heterozygous gain-of-function (GOF) mutations of hypoxia-inducible factor 2α (HIF2A), a significant regulator of hypoxia sensing, are associated with erythrocytosis, thrombosis and vascular complications that account for morbidity and mortality of patients with these disorders. We demonstratethat 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, the HIF2A-SMCs, but not HIF2A-ECs, were phenotypically aberrant, more contractile and stiffer, and overexpressed endothelin 1(EDN1), myosin heavy chain, elastin and fibrillin. EDN1 inhibition or knockdown of EDN1-receptors reduced HIF2-SMC stiffness. Hif2A GOF heterozygous mice displayed early onset of pulmonary hypertension, had SMCs with more disorganized stress fibers and higher stiffness in their pulmonary arterial vascular smooth muscle cells, and more deformable main pulmonary arteries compared with wild type mice. We propose that targeting these vascular aberrations may benefit patients with HIF2A GOF and other conditions ofaugmented hypoxia signaling.
Chan, Xin and Eoh, Joon and Volkova, Eugenia and Black, Rebecca and Fang, Lilly and Gorashi, Rayyan and Song, Jihyun and Wang, Jing and Elliott, Morgan and Barreto-Ortiz, Sebastian F. and Chen, James and Lin, Brian L. and Santhanam, Lakshmi and Cheng, Linzhao and Lee, Frank S. and Prchal, Josef T. and Gerecht, Sharon, HIF2A Gain-of-Function Mutation Modulates the Stiffness of Smooth Muscle Cells and Compromises Vascular Mechanics. Available at SSRN: https://ssrn.com/abstract=3553545 or http://dx.doi.org/10.2139/ssrn.3553545
This version of the paper has not been formally peer reviewed.
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