Abstract 4368485: BMP3 Overexpression Attenuates Pulmonary Arterial Hypertension

Abstract

Backgound: Pulmonary arterial hypertension (PAH), a rare and progressive subtype of pulmonary hypertension (PH), leads to right heart failure and, ultimately, death. PH is defined by a mean pulmonary arterial pressure greater than 20 mmHg at rest, assessed via right heart catheterization. Methods: We investigated BMP3 expression in lung tissues from multiple animal models of PAH (mice, rats, pigs) and in pulmonary vascular cells from PAH patients. Functional studies were conducted using hPASMCs and hPAECs from healthy individuals and PAH patients. BMP3 loss- and gain-of-function models were generated via genetic deletion and BMP3 overexpression (recombinant protein and AAV1-mediated gene transfer). Phenotypic effects were assessed using hemodynamics, MRI, and histological analyses. Results: BMP3 was primarily expressed in PASMCs and found to be downregulated in PAH. Loss of BMP3 in PASMC enhanced the proliferation and migration of hPAEC, whereas BMP3 overexpression in PASMC restored endothelial function. Both global and SMC-specific BMP3 knockout mice exhibited worsened pulmonary vascular remodeling and right ventricular dysfunction in response to PAH stimuli. Therapeutically, systemic BMP3 administration and lung-specific AAV1-BMP3 delivery inhibited PAH. Mechanistically, BMP3 activated the protective BMP/Smad1/5/8 signaling pathway while suppressing the pro-fibrotic TGF-β/Smad2/3 pathway. Conclusion: BMP3 is a critical modulator of pulmonary vascular and cardiac remodeling in PAH. Restoration of BMP3 signaling offers a promising therapeutic avenue by rebalancing BMP and TGF-β pathways through paracrine cell-cell interactions.