CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension
| Autor: | S.R. Yang, Xiao Teng, Jing Feng, Xiyun Yan, Xuehui Chen, Zheng Liu, Lingling Zhang, Yongting Luo, Jianan Chen, Shuai Zhao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male General Physics and Astronomy 02 engineering and technology Severity of Illness Index Muscle Smooth Vascular Pathogenesis Mice Myocyte Medicine lcsh:Science Cells Cultured Feedback Physiological Mice Knockout Multidisciplinary Monocrotaline 021001 nanoscience & nanotechnology Publisher Correction Cell Hypoxia Up-Regulation Hypertension CD146 0210 nano-technology Reprogramming Science Hypertension Pulmonary Myocytes Smooth Muscle Primary Cell Culture CD146 Antigen Pulmonary Artery Vascular Remodeling General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Downregulation and upregulation medicine.artery Animals Humans Pulmonary pathology Respiratory tract diseases business.industry General Chemistry medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Pulmonary hypertension Rats Disease Models Animal 030104 developmental biology Pulmonary artery Cancer research lcsh:Q business |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Vascular remodelling contributes to the development of pulmonary hypertension (PH). Here Luo and colleagues find that increases in CD146 levels drive vascular remodelling in PH through a cross-talk with hypoxia inducible factor (HIF) signalling, and show that inhibition of CD146 can attenuate disease progression. |
| Databáze: | OpenAIRE |
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