HIF2A gain-of-function mutation modulates the stiffness of smooth muscle cells and compromises vascular mechanics

• DOI: 10.1016/j.isci.2021.102246
• Publication Date: 2021-03-02T17:25:19Z
• Authors: Xin Yi Chan; Eugenia Volkova; Joon Eoh; Rebecca Black; Lilly Fang; Rayyan Gorashi; Jihyun Song; Jing Wang; Morgan B. Elliott; Sebastian F. Barr...; James Chen; Brian L. Lin; Lakshmi Santhanam; Linzhao Cheng; Frank S. Lee; Josef T. Prchal; Sharon Gerecht
• Keywords: Hypoxia

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 mortality patients. We demonstrated the pathology HIF2A GOF is independent erythrocytosis. generated GOF-induced pluripotent stem cells (iPSCs) differentiated them into endothelial (ECs) smooth muscle (SMCs). Unexpectedly, HIF2A-SMCs, but not HIF2A-ECs, were phenotypically aberrant, more contractile, stiffer, overexpressed endothelin 1 (EDN1), myosin heavy chain, elastin, fibrillin. EDN1 inhibition knockdown EDN1-receptors both reduced HIF2-SMC stiffness. Hif2A heterozygous mice displayed pulmonary hypertension, had SMCs disorganized stress fibers higher stiffness in their arterial cells, deformable arteries compared wild-type mice. Our findings suggest targeting these aberrations could benefit patients conditions augmented hypoxia signaling.