CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension

Nature Communications
Yongting LuoXiyun Yan

Abstract

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of cardiopulmonary units. No cure is currently available due to an incomplete understanding of vascular remodeling. Here we identify CD146-hypoxia-inducible transcription factor 1 alpha (HIF-1α) cross-regulation as a key determinant in vascular remodeling and PAH pathogenesis. CD146 is markedly upregulated in pulmonary artery smooth muscle cells (PASMCs/SMCs) and in proportion to disease severity. CD146 expression and HIF-1α transcriptional program reinforce each other to physiologically enable PASMCs to adopt a more synthetic phenotype. Disruption of CD146-HIF-1α cross-talk by genetic ablation of Cd146 in SMCs mitigates pulmonary vascular remodeling in chronic hypoxic mice. Strikingly, targeting of this axis with anti-CD146 antibodies alleviates established pulmonary hypertension (PH) and enhances cardiac function in two rodent models. This study provides mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy for PAH through direct modulation of CD146-HIF-1α cross-regulation.

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Citations

Aug 9, 2020·International Journal of Molecular Sciences·Chiara Corrado, Simona Fontana
Jun 23, 2020·Oxidative Medicine and Cellular Longevity·Damian GajeckiAdrian Doroszko
Sep 4, 2020·The Journal of Clinical Investigation·Soni Savai PullamsettiRajkumar Savai
Mar 7, 2021·International Journal of Molecular Sciences·Ronni BaranMarkus Wehland
Mar 20, 2021·Cardiovascular Research·Andrea CignarellaMatthias Barton
Jun 3, 2021·Antioxidants·Daria S Kostyunina, Paul McLoughlin
Nov 23, 2021·Frontiers in Pharmacology·Yang-Yang HeZhi-Yan Han

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Methods Mentioned

BETA
pharmacotherapies
immunoprecipitation
ChIP
PCR
fluorescence-activated cell sorting
transfection
Assay
electrophoresis
protein assay

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