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

Yongting Luo (), Xiao Teng, Lingling Zhang, Jianan Chen, Zheng Liu, Xuehui Chen, Shuai Zhao, Sai Yang, Jing Feng and Xiyun Yan ()
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Yongting Luo: China Agricultural University
Xiao Teng: Chinese Academy of Medical Sciences and Peking Union Medical College
Lingling Zhang: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Jianan Chen: Institute of Biophysics, Chinese Academy of Sciences
Zheng Liu: Institute of Biophysics, Chinese Academy of Sciences
Xuehui Chen: Institute of Biophysics, Chinese Academy of Sciences
Shuai Zhao: Institute of Biophysics, Chinese Academy of Sciences
Sai Yang: Institute of Biophysics, Chinese Academy of Sciences
Jing Feng: Institute of Biophysics, Chinese Academy of Sciences
Xiyun Yan: Institute of Biophysics, Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11500-6

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