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

Xin Yi Chan; Eugenia Volkova; Joon Eoh; Rebecca Black; Lilly Fang; Rayyan Gorashi; Jihyun Song; Jing Wang; Morgan B. Elliott; Sebastian F. Barreto-Ortiz; James Chen; Brian L. Lin; Lakshmi Santhanam; Linzhao Cheng; Frank S. Lee; Josef T. Prchal; Sharon Gerecht

iScience (Apr 2021)

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

Xin Yi Chan,
Eugenia Volkova,
Joon Eoh,
Rebecca Black,
Lilly Fang,
Rayyan Gorashi,
Jihyun Song,
Jing Wang,
Morgan B. Elliott,
Sebastian F. Barreto-Ortiz,
James Chen,
Brian L. Lin,
Lakshmi Santhanam,
Linzhao Cheng,
Frank S. Lee,
Josef T. Prchal,
Sharon Gerecht

Affiliations

Xin Yi Chan: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Eugenia Volkova: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Joon Eoh: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Rebecca Black: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Lilly Fang: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Rayyan Gorashi: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Jihyun Song: Hematology, University of Utah School of Medicine and Huntsman Cancer Center, Salt Lake City, UT 84132, USA
Jing Wang: Division of Hematology and Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Morgan B. Elliott: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Sebastian F. Barreto-Ortiz: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
James Chen: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Brian L. Lin: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
Lakshmi Santhanam: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Linzhao Cheng: Division of Hematology and Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Frank S. Lee: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 605 Stellar Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA
Josef T. Prchal: Hematology, University of Utah School of Medicine and Huntsman Cancer Center, Salt Lake City, UT 84132, USA
Sharon Gerecht: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author

Journal volume & issue: Vol. 24, no. 4
p. 102246

Abstract

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Summary: 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 EDN1-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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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