Paracrine action of bone morphogenetic protein 3 in pulmonary arterial hypertension

ABSTRACT Background Despite recent advancements in the management of pulmonary arterial hypertension (PAH), the disease remains devastating, with limited survival. Although the Bone Morphogenetic Protein (BMP) signaling pathway is known to play an important role in PAH, our current understanding of this pathway remains limited. Methods We assessed BMP3 levels in the lungs of mice, rats, and pigs with pulmonary hypertension, and in pulmonary vascular cells from human patients with PAH. We performed in vitro studies on human pulmonary artery smooth muscle cells (hPASMCs) and human pulmonary artery endothelial cells (hPAECs) derived from healthy donors and from patients with PAH. We generated mice with global or SMC-specific deletion of BMP3. Recombinant BMP3 protein and adeno-associated viruses (AAV) were used to overexpress BMP3 in two different models of PAH in rodents. Magnetic resonance imaging, cardiac hemodynamics, morphometric, and histological measurements were performed to evaluate the effects of BMP3 on cardiac function and pulmonary vascular remodeling. Results BMP3 is predominantly expressed in PASMCs and is downregulated in PAH. In vitro, conditioned medium from siRNA-BMP3-transfected hPASMCs increased hPAECs migration and proliferation, while PASMC-derived BMP3 inhibited PAH-diseased PAEC dysfunction. In both global and SMC-specific BMP3-deficient mice, exposure to a model of PAH exacerbated cardiac and pulmonary vascular remodeling in middle-aged mice. An intraperitoneally injected recombinant BMP3 prevented and reversed PAH in mice. A lung-targeted overexpression of BMP3, via AAV1-BMP3, reversed pulmonary vascular remodeling and inhibited cardiac dysfunction in mice and rats. Mechanistically, BMP3 activated the BMP/Smad1,5,8 pathway, inhibited the TGF-β/Smad2,3 pathway, and decreased the expression of cell cycle genes in hPAECs and in the lungs of BMP3-treated animals with PAH. Conclusions Our findings provide evidence that BMP3 overexpression attenuates pulmonary vascular remodeling and inhibits cardiac dysfunction by restoring the balance between the TGF-β and BMP pathways through a cell-cell communication mechanism, offering a novel therapeutic pathway for PAH. Clinical Perspective What is New? BMP3 is downregulated in the lungs of mice, rats, and pigs with pulmonary hypertension and in pulmonary artery smooth muscle cells of patients with PAH. BMP3 acts as a paracrine factor between pulmonary vascular cells. Overexpression of BMP3 decreases pulmonary vascular remodeling and reverses cardiac dysfunction in PAH-diseased rodents. BMP3 acts by restoring the balance between the TGF-β/Smad2,3 pathway and the BMP/Smad1,5,8 pathway What Are the Clinical Implications? BMP3 represents a promising disease-modifying agent with potential for clinical translation in the treatment of PAH. Overexpressing BMP3 with Adeno-Associated Viruses has therapeutic potential to treat PAH.