BONE MORPHOGENETIC PROTEIN 9 PROMOTES HYPERTENSION BY INDUCING VASCULAR REMODELING THROUGH REGULATING SMOOTH MUSCLE CELL INFLAMMATION AND OXIDATIVE STRESS

Objective: Hypertension is the most important risk factor for cardiovascular disease and death. However, the mechanism of hypertension has not been fully clarified. Bone morphogenetic protein 9 (BMP9) is known as an important regulator of vascular homeostasis. Recent studies have found that mutations in the gene encoding BMP9 are associated with elevated systolic blood pressure. Therefore, we studied the role of BMP9 in promoting hypertension.Design and method: The expressional profiles of BMP9 in plasma samples of hypertensive subjects and controls were determined by enzyme-linked immunosorbent assay. BMP9 transgenic rats (Tg) were constructed to analyze the function of BMP9. The blood pressure levels were measured using the tail-cuff system and radiotelemetry methods. The role of BMP9 in vascular remodeling was determined by vascular relaxation studies. Results: Circulating BMP9 concentrations, as determined by enzyme-linked immunosorbent assay, were significantly higher in hypertensive patients than in controls (251.07 ± 54.66 vs. 226.08 ± 56.70 pg/mL; P < 0.01). We found that the blood pressure levels of Tg rats were significantly higher than those littermates wild-type rats (WT). Besides, BMP9 overexpression caused dysfunctional vasoconstriction and vasodilation, remodeling of arterial walls, and increased vascular superoxide stress, inflammation, and collagen deposition. These findings indicate that BMP9 is a prohypertensive factor that directly promotes vascular remodeling. In order to explore the possible mechanism of the increase of blood pressure caused by BMP9, immunofluorescence staining method was used to detect the expression of BMP9 in vascular tissues. The results showed that BMP9 expression was increased and predominantly located in vascular smooth muscle cells (VSMC). In vitro, BMP9 improves contraction, proliferation, and migration in human artery smooth muscle cells (HASMC). Conclusions: BMP9 acts on vascular smooth muscle, promoting vascular oxidative stress, inflammation and collagen deposition, leading to vascular remodeling and dysfunction, resulting in increased blood pressure. BMP9 may be a novel therapeutic target against pathological hypertension.