HIF2A gain-of-function mutation modulates the stiffness of smooth muscle cells and compromises vascular mechanics
| Autor: | Rayyan Gorashi, Lilly Fang, Morgan B. Elliott, Joon Eoh, Josef T. Prchal, Jing Wang, Brian L. Lin, James K. Chen, Rebecca Black, Jihyun Song, Sharon Gerecht, Lakshmi Santhanam, Eugenia Volkova, Frank S. Lee, Linzhao Cheng, Xin Yi Chan, Sebastian F. Barreto-Ortiz |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Science Biophysics 02 engineering and technology Pathophysiology Article 03 medical and health sciences Myosin medicine Biomechanics Induced pluripotent stem cell Gene knockdown Multidisciplinary biology business.industry Hypoxia (medical) musculoskeletal system 021001 nanoscience & nanotechnology medicine.disease Pulmonary hypertension Endothelin 1 030104 developmental biology Cancer research biology.protein medicine.symptom 0210 nano-technology business Fibrillin Elastin |
| Zdroj: | iScience, Vol 24, Iss 4, Pp 102246-(2021) iScience |
| ISSN: | 2589-0042 |
| Popis: | 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. Graphical abstract Highlights • HIF2-SMCs are stiffer than WT-SMCs and differ in contractile SMC marker expression • HIF2-SMCs and WT-SMCs differ in EDN1 production and ECM composition • HIF- 2α induces EDN1; EDNI subsequently induces SMC stiffening • Hif2A GOF mouse arterial SMCs have more disorganized stress fibers and are stiffer Pathophysiology; Biophysics; Biomechanics |
| Databáze: | OpenAIRE |
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