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HIF2A Gain-of-Function Mutation Modulates the Stiffness of Smooth Muscle Cells and Compromises Vascular Mechanics

37 Pages Posted: 13 Mar 2020 Publication Status: Published

See all articles by Xin Chan

Xin Chan

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

Joon Eoh

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

Eugenia Volkova

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

Rebecca Black

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

Lilly Fang

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

Rayyan Gorashi

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

Jihyun Song

University of Utah

Jing Wang

Johns Hopkins University - Institute for Cell Engineering

Morgan Elliott

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

Sebastian F. Barreto-Ortiz

Johns Hopkins University - Department of Anesthesiology and Critical Care Medicine

James Chen

Johns Hopkins University - Department of Anesthesiology and Critical Care Medicine

Brian L. Lin

Johns Hopkins Medical Institutions - Division of Cardiology

Lakshmi Santhanam

Johns Hopkins University - Department of Anesthesiology and Critical Care Medicine

Linzhao Cheng

Johns Hopkins University - Institute for Cell Engineering

Frank S. Lee

University of Pennsylvania

Josef T. Prchal

University of Utah

Sharon Gerecht

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

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Abstract

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.

Keywords: HIF2A, hypoxia, smooth muscle cells, differentiation, vascular mechanics, induced pluripotent stem cells, erythrocytosis/polycythemia

Suggested Citation

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.

Xin Chan

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

United States

Joon Eoh

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

United States

Eugenia Volkova

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

United States

Rebecca Black

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

United States

Lilly Fang

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

United States

Rayyan Gorashi

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

United States

Jihyun Song

University of Utah

1645 E. Campus Center
Salt Lake City, UT 84112
United States

Jing Wang

Johns Hopkins University - Institute for Cell Engineering

United States

Morgan Elliott

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

United States

Sebastian F. Barreto-Ortiz

Johns Hopkins University - Department of Anesthesiology and Critical Care Medicine

Baltimore, MD
United States

James Chen

Johns Hopkins University - Department of Anesthesiology and Critical Care Medicine

Baltimore, MD
United States

Brian L. Lin

Johns Hopkins Medical Institutions - Division of Cardiology

550 N. Broadway
Baltimore, MD 21205
United States

Lakshmi Santhanam

Johns Hopkins University - Department of Anesthesiology and Critical Care Medicine

Baltimore, MD
United States

Linzhao Cheng

Johns Hopkins University - Institute for Cell Engineering

United States

Frank S. Lee

University of Pennsylvania

Philadelphia, PA 19104
United States

Josef T. Prchal

University of Utah

1645 E. Campus Center
Salt Lake City, UT 84112
United States

Sharon Gerecht (Contact Author)

Johns Hopkins University - Department of Chemical and Biomolecular Engineering

United States

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