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.
Highlights
Treatment in the last decade, Pulmonary arterial hypertension (PAH) diagnosis is commonly associated with extremely poor prognosis, worse than many cancers[4]
In our study, we identified previously unappreciated hypoxic reprogramming involving the cross-regulation between CD146 and HIF-1α as a crucial process in governing the switch of PASMCs toward a more-synthetic phenotype
On the basis of these observations, we propose that CD146-HIF-1α axis might serve as an attractive therapeutic target for pulmonary hypertension (PH)
Summary
Treatment in the last decade, PAH diagnosis is commonly associated with extremely poor prognosis, worse than many cancers[4]. Existing treatments predominantly target vasoconstriction through vasodilators involving prostanoids, endothelin receptor blockers, and/or phosphodiesterase-5 inhibitors[5,6] These medications provide symptomatic relief, they only modestly improve survival as they are unable to prevent excessive SMC burden and occlusive remodeling[7]. Mice with Hif1a heterozygous inactivation or inducible deletion in SMCs exhibit reduced vascular remodeling and blunted PASMC hypertrophy in chronic hypoxic mice[11,12] In support of this observation, HIF-1α has been implicated in clonal expansion of hypoxia-primed SMC progenitors that govern muscularization during hypoxic PH13. HIF-1α functions as an intrinsic pathogenic determinant in chemically induced and genetic forms of PH14–16 These studies indicate that controlling HIF-1α-driven vascular remodeling may provide a promising avenue for PAH pharmacotherapies. Studies in vascular cells suggested that a possible link exists between CD146 expression and HIF-1α activation[24,25,26]
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