BMP9 as a major regulator of vascular tone in Pulmonary Arterial Hypertension: a promising new therapeutic target – B9inPAH

Cardiovascular diseases are a major economic burden on health care systems and represent one of the leading causes of global mortality and morbidity. These recent years have demonstrated the fundamental role played by BMPs (Bone morphogenetic proteins) in cardiac and vascular development, and that defects in the BMP signaling pathway result in a large number of cardiovascular diseases. Although new biomedical therapeutics targeting BMPs or the BMP signaling pathway hold promise in future treatment strategies for these life-threatening diseases, our current understanding of the molecular signaling pathways activated by BMPs and their exact pathogenic roles remains limited.
Among BMPs (> 30), it is now well established that BMP9 and BMP10 are crucial in normal vascular development, and perturbation in the BMP9/BMP10 signaling pathway has emerged as essential in endothelial (dys)function and vascular remodeling. Indeed, in 2007, our team was the first to identify that BMP9 and BMP10 are two high affinity ligands for activin receptor-like kinase 1 (ALK1) and BMP receptor type II (BMPR2), two key BMP receptor mainly expressed on vascular endothelial cells (ECs). Furthermore, specific heterozygous germline mutations in genes coding for these two key receptors and more recently in BMP9 are involved in two rare vascular diseases: The Rendu-Osler syndrome (HHT for hemorrhagic hereditary telangiectasia) and pulmonary arterial hypertension (PAH).
The objective of the proposal is to determine the role of BMP9 in cardiovascular pathologies. Our in vitro and in vivo data indicate that BMP9 has a pulmonary vasoconstrictive action that contributes to the development and progression of the pulmonary vascular remodeling associated to PAH and thus BMP9 could be a new interesting therapeutic target for these severe cardiovascular conditions. This hypothesis is based on published and unpublished data showing that knockout (KO) mice for Bmp9 are less susceptible to the development of pulmonary hypertension (PH)-induced by chronic hypoxia and by monocrotaline (MCT)-pyrrole. Since mice generally display modest vascular remodeling compared to rats, one of our objectives will therefore seek to validate these findings in Bmp9-KO rats in order to obtain a more complete assessment of hemodynamic profile in these animals.
To decipher the molecular mechanisms by which BMP9 exerts its pulmonary vasoconstrictive action, we have chosen to focus on PAH. Indeed, experimental mouse and rat models are available for this pathology and we have developed a repertoire of unique tools including Bmp9-KO rats (created using the CRISPR-Cas9 system) and primary cultures of PAH-derived human pulmonary endothelial cells (ECs) carrying mutations in ALK1 and BMPR2 from explanted lungs. These tools will rapidly give us the opportunity to better understand the signaling through which BMP9 exerts its potent vasoconstrictive action in the pulmonary vasculature (we have already identified endothelin-1 and apelin as potential factors regulated by BMP9, both in vivo and in vitro). Since submission of our letter of intent, we have obtained very convincing results that support our hypothesis. We found that injection of the soluble form of ALK1 (ALK1ecd) in the monocrotaline-injected PH model under a curative protocol significantly protect rats against the development of PH. One objective of this project is to validate this result in other PAH models using different approaches to block BMP9. This is a rather counter-intuitive therapeutic approach as it goes against the straightforward hypothesis that PAH should be treated by adding more ligands.
Together, this project should provide a better understanding of the BMP signaling pathway and a new therapeutic approach to cure PAH patients, but also HHT and any other cardiovascular disease involving the BMP signaling pathway.