Role of bone morphogenic protein-4 in gestational diabetes mellitus-related hypertension.

Hyperglycaemia stimulates the synthesis and release of bone morphogenetic protein-4 (BMP-4) in vascular endothelial cells, which further induces peroxide production and inflammatory responses, leading to vascular endothelial dysfunction. However, the role of BMP-4 in gestational diabetes mellitus (GDM)-related vascular endothelial dysfunction remains unclear. In the present study, the hypothesis that the overexpression of BMP-4 would induce GDM-related hypertension by impairing vascular endothelial function was evaluated. An animal model of GDM was established in Sprague-Dawley (SD) rats. Based on blood pressure, rats were divided into control, GDM and GDM + hypertension (HT) groups. The expression levels of BMP-4, cyclooxygenase-2 (COX-2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX-1) and vascular cell adhesion molecule 1 (VCAM-1) in the endothelium of the abdominal aorta of rats in each group were determined via immunohistochemistry and western blotting. Pregnant SD rats were divided into four groups, separately infused with BMP-4, BMP-4 + noggin, noggin or vehicle by osmotic pumps, and blood pressure and vasorelaxation were examined. Immunohistochemistry indicated that the expression levels of the four proteins were lower in the control group than in the GDM and GDM + HT groups. The positive expression rate of VCAM-1 was significantly lower in the control group than in the GDM and GDM+HT groups, and the differences were statistically significant (χ2=17.325, P<0.05; χ2=10.080, P<0.05). Western blotting revealed that the expression level of the COX-2 protein exhibited a sequential increase in the three groups. The expression level of COX-2 in the control and GDM groups was significantly lower than that in the GDM+HT group (3.358±1.286; P<0.05 and P<0.05, respectively). The expression level of VCAM-1 protein in the three groups also exhibited a significant sequential increase (F=31.732; P≤0.001). The expression level of VCAM-1 in the control and GDM groups was significantly lower than that in the GDM+HT group (2.698±0.223; P≤0.001 and P≤0.001, respectively). Infusion of BMP-4 increased systolic blood pressure (from 82 to 112 mmHg) and impaired vasorelaxation in pregnant SD rats after 2 weeks. Co-treatment with noggin completely blocked BMP-4-induced effects. Thus, the BMP-4/NOX-1/COX-2 signalling pathway may be involved in GDM-related hypertension, but VCAM-1 may be substantially associated with GDM-related hypertension. Furthermore, overexpression of BMP-4 could lead to hypertension by impairing endothelial function in pregnancy.