Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling
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Published:2024-01-19
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ISSN:1469-3178
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Container-title:EMBO Reports
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language:en
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Short-container-title:EMBO Rep
Author:
Kim Hyunbum, Liu YuORCID, Kim Jiwon, Kim YunhyeORCID, Klouda Timothy, Fisch Sudeshna, Baek Seung Han, Liu Tiffany, Dahlberg Suzanne, Hu Cheng-JunORCID, Tian Wen, Jiang XinguoORCID, Kosmas KosmasORCID, Christou Helen AORCID, Korman Benjamin D, Vargas Sara OORCID, Wu Joseph CORCID, Stenmark Kurt RORCID, Perez Vinicio de JesusORCID, Nicolls Mark RORCID, Raby Benjamin A, Yuan KeORCID
Abstract
AbstractVascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world’s most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.
Funder
HHS | NIH | National Heart, Lung, and Blood Institute American Thoracic Society Bayer HHS | NIH | NHLBI | NHLBI Division of Intramural Research
Publisher
Springer Science and Business Media LLC
Subject
Genetics,Molecular Biology,Biochemistry
Reference66 articles.
1. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M (2010) Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 121:2747–54 2. Baek SH, Maiorino E, Kim H, Glass K, Raby BA, Yuan K (2022) Single cell transcriptomic analysis reveals organ specific pericyte markers and identities. Front Cardiovasc Med 9:876591 3. Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 7:452–64 4. Bordenave J, Thuillet R, Tu L, Phan C, Cumont A, Marsol C, Huertas A, Savale L, Hibert M, Galzi JL, Bonnet D, Humbert M, Frossard N, Guignabert C (2020) Neutralization of CXCL12 attenuates established pulmonary hypertension in rats. Cardiovasc Res 116:686–697 5. Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, Carmeliet P (2003) Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Investig 111:1519–27
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