2. Academic Validation
  3. CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension

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

  • Nat Commun. 2019 Aug 7;10(1):3551. doi: 10.1038/s41467-019-11500-6.
Yongting Luo 1,  Xiao Teng 2,  Lingling Zhang 3,  Jianan Chen 4,  Zheng Liu 4,  Xuehui Chen 4,  Shuai Zhao 4,  Sai Yang 5,  Jing Feng 4,  Xiyun Yan 6
Affiliations

Affiliations

  • 1 Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Yuanmingyuan West Road 2, 100193, Beijing, China. [email protected].
  • 2 State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 North Lishi Road, 100037, Beijing, China.
  • 3 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, 100730, Beijing, China.
  • 4 Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, 100101, Beijing, China.
  • 5 Laboratory Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, 100101, Beijing, China.
  • 6 Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, 100101, Beijing, China. [email protected].
PMID: 31391533 DOI: 10.1038/s41467-019-11500-6
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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