Abstract Background Pulmonary arterial hypertension (PAH) is a rare, progressive form of pulmonary hypertension (PH) that ultimately leads to right heart failure and death. PH is clinically defined by a mean pulmonary arterial pressure 20 mmHg at rest as measured by right heart catheterization. Methods We assessed BMP3 expression in lung tissues from several PAH animal models (mice, rats, pigs) and in pulmonary vascular cells derived from PAH patients. Functional studies were performed in hPASMCs and hPAECs from healthy donors and PAH patients. BMP3 loss- and gain-of-function approaches included genetic deletion as well as BMP3 overexpression using recombinant protein and AAV1-mediated gene delivery. Disease phenotypes were evaluated using hemodynamic measurements, MRI, and histopathology. Results BMP3 was predominantly expressed in PASMCs and was markedly reduced in PAH. BMP3 deficiency in PASMCs promoted hPAEC proliferation and migration, whereas BMP3 overexpression restored endothelial function. Both global and SMC-specific BMP3 knockout mice displayed aggravated pulmonary vascular remodeling and right ventricular dysfunction under PAH conditions. In contrast, systemic BMP3 supplementation and lung-targeted AAV1-BMP3 expression attenuated PAH development. Mechanistically, BMP3 enhanced protective BMP/Smad1/5/8 signaling while suppressing the pro-fibrotic TGF-β/Smad2/3 axis. Conclusion BMP3 serves as a key regulator of pulmonary vascular remodeling and cardiac pathology in PAH. Restoring BMP3 signaling represents a promising therapeutic strategy by reestablishing the balance between BMP- and TGF-β-dependent pathways via paracrine intercellular communication. This abstract is funded by: NIH
Halouani et al. (Fri,) studied this question.