Targeting the CD146-HIF-1α axis with anti-CD146 antibodies or genetic ablation mitigated pulmonary vascular remodeling and alleviated established pulmonary hypertension in rodent models.
Targeting the CD146-HIF-1α cross-regulation axis mitigates pulmonary vascular remodeling and alleviates pulmonary hypertension in rodent models, offering a potential therapeutic strategy for PAH.
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.
Luo et al. (Wed,) conducted a other in Pulmonary arterial hypertension. Anti-CD146 antibodies or genetic ablation of Cd146 vs. Control antibody or Wild-type was evaluated on Pulmonary vascular remodeling and right ventricular systolic pressure (RVSP). Targeting the CD146-HIF-1α axis with anti-CD146 antibodies or genetic ablation mitigated pulmonary vascular remodeling and alleviated established pulmonary hypertension in rodent models.
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