Bone morphogenetic protein 12: a novel target for cardiovascular disease

Bone morphogenetic protein 12 (BMP12) is known to regulate mesenchymal differentiation and extracellular matrix remodeling. Given its structural and signaling similarities to BMP2, which promotes osteogenic phenotypic switching and pro-atherogenic responses in vascular smooth muscle cells (VSMCs), BMP12 may also contribute to vascular remodeling and atherosclerosis progression. This translational study aimed to unravel BMP12 involvement in cardiovascular disease (CVD). BMP12 effects on atherogenesis-related processes in VSMCs in absence or presence of BMP type I receptor inhibitors (DMH2 and LDN-193189) were evaluated. Additionally, circulating BMP12 levels were measured in a well-characterized cohort of patients with CV risk factors and correlated with cardiometabolic disorders and vascular damage markers. Results from the experimental study showed increased migration and calcification in BMP12-treated VSMCs. Mechanistically, BMP12 induced expression of osteogenic markers (RUNX2 and ALP) and genes related to cellular migration (Mmp9), while reducing contractile marker Desmin. These pro-atherogenic effects were blocked using BMP type I receptor inhibitors. Furthermore, the clinical study revealed higher serum BMP12 levels in patients with CVD and type 2 diabetes. Moreover, circulating BMP12 concentrations were elevated in patients with carotid and femoral plaques, correlating with plaque volume. Notably, BMP12 emerged as an independent predictor of femoral atherosclerosis. Collectively, these findings identify BMP12 as a previously unrecognized mediator of vascular remodeling, promoting pro-atherogenic effects in VSMCs through canonical BMP signaling. The association between elevated circulating BMP12 levels and subclinical vascular damage further supports its potential value as a contributor to atherosclerosis progression and as a promising novel candidate biomarker for CV risk.