Pulmonary arterial hypertension (PAH) is a rare, incurable, and lethal cardiopulmonary disease that impairs both the structure and function of the blood vessels of the heart and lungs. Although its mechanisms remain largely unknown, several genetic predisposition factors have been identified, in particular mutations affecting the BMPRII/ALK1 signaling pathway. More recently, mutations in the genes encoding two major ligands of this pathway, BMP9 (also known as GDF2) and BMP10, have been detected in patients. These two proteins share a high degree of sequence identity and bind with high affinity to the endothelial receptor ALK1, but their expression profiles differ: BMP9 is mainly produced by hepatic stellate cells, whereas BMP10 is produced essentially by the heart. Their respective roles in the pathophysiology of the disease, however, remained poorly understood.
To clarify this, the authors generated mouse models deficient in Bmp9 (constitutive deletion) and/or Bmp10 (tamoxifen-inducible deletion), yielding both single and double knockouts. Single-deficient mice did not develop any overt age-related phenotype compared with wild-type animals. In contrast, combined deficiency of the two genes led to vascular abnormalities: decreased peripheral vascular resistance and blood pressure, progressive development of high-output heart failure, and pulmonary hemosiderosis. Transcriptomic analysis (RNA-seq) of the lungs of these double knockouts revealed differential expression of genes related to inflammation and vascular homeostasis, with confirmed overexpression of inflammatory chemokines such as CCL2 and CCL3.
When subjected to chronic hypoxia, however, these mice revealed specific roles for each ligand. After three weeks of exposure, Bmp10-deficient mice exhibited an enlarged heart, with no change in the muscularization of the pulmonary arterioles. Conversely, deletion of Bmp9, in both single and double knockouts, attenuated hypoxia-induced pulmonary vascular remodeling. Consistent with these observations, endothelin-1 levels were significantly reduced in Bmp9-deficient mice, but not in Bmp10-deficient mice. Moreover, in a chicken chorioallantoic membrane model, the vasoconstrictor effect of BMP9 was abolished by bosentan, an endothelin receptor antagonist.
This work thus establishes redundant roles for BMP9 and BMP10 in cardiovascular homeostasis under normoxic conditions—only the double deletion causing severe abnormalities—but distinct functions under chronic hypoxia, with BMP9 contributing to pulmonary vascular remodeling and BMP10 to cardiac remodeling. The authors emphasize that a limitation of this mouse model lies in the moderate PAH that develops, without plexiform lesions, and call for caution regarding therapeutic strategies targeting this pathway, in terms of specificity, dose, and duration of treatment.