The Study Of Correlation Between BMP-4 And Gestational Diabetes Mellitus Related Hypertension

Purpose:Gestational diabetes mellitus(GDM)is defined as hyperglycaemia first diagnosed during pregnancy,which is known to not only significantly increase the incidence of macrosomia,dystocia,and operative delivery,but also be closely associated with various adverse pregnancy outcomes and long-term health risks,such as miscarriage,foetal malformations,intrauterine death and development of type 2 diabetes in the mother and child.Bone morphogenetic protein-4(BMP-4)is a member of the transforming growth factor-?superfamily that plays important roles in embryonic development,angiogenesis,and chondrogenesis.Recent studies have found that hyperglycaemia can stimulate the synthesis and release of BMP-4 in the vascular endothelium.BMP-4 has been demonstrated to exhibit high affinity for its type 1 receptors.After binding,Nox1-dependent reduced nicotinamide adenine dinucleotide phosphate(NADPH)oxidase(NOX-1)is activated,stimulating the synthesis of reactive oxygen species(ROS).Increased intracellular ROS can upregulate cyclooxygenase-2(COX-2)expression as well as releasing prostaglandin 2?(PGF2?),thereby causing endothelium-dependent vasoconstriction and blocking endothelium-dependent vasodilation.Additionally,the increase in BMP-4 can activate the expression of vascular cell adhesion molecule 1(VCAM-1),which induces vascular endothelial inflammation and subsequent exacerbation of vascular endothelial dysfunction,thereby causing systemic vasoconstriction and multi-organ ischaemia,which results in elevated blood pressure and multiple organ damage.Preeclampsia is the main cause of maternal and foetal morbidity and mortality.The aetiology of preeclampsia remains elusive.However,GDM and preeclampsia share many risk factors.Moreover,GDM is even considered a risk factor for preeclampsia.Several theories suggest that endothelial dysfunction occurs in GDM as well as preeclampsia.Accordingly,we speculated that BMP-4 may be involved in the pathogenesis of GDM related hypertension through impairment of endothelial function.The correlation between BMP-4 and GDM remains unclear.In this study,we investigated the expression of BMP-4 related proteins and Vcam-1 in the pathogenesis of GDM related hypertension and their effects in vascular endothelial function.Experimental Design: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 of Bmp-4,Cox-2,Nox-1,and Vcam-1in the endothelium of the abdominal aorta of rats in each group was determined via immunohistochemistry and western blotting.Pregnant SD rats were divided into four groups,separately infused with BMP-4,BMP-4+NOGGIN,NOGGIN,and vehicle by osmotic pumps,and the blood pressure and vasorelaxation were examined in the four groups.Results:Immunohistochemistry showed that the expression of the four proteins was 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(?~2=17.325,p<0.05;?~2=10.08,p<0.05).Western blotting revealed that the expression level of the Cox-2 protein exhibited a sequential increasein the three groups.The expression 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 levels 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 the systolic blood pressure in pregnant SD rats(from 82 to 112 mm Hg)after 2 weeks and impaired vasorelaxation.Co-treatment with NOGGIN completely blocked BMP-4-induced effects.Conclusion:Bmp-4/Nox-1/Cox-2 pathway might be involved in GDM-related hypertension,but Vcam-1 might be substantially associated with GDM-related hypertension.Furthermore,overexpression of BMP-4 could lead to hypertension by impairing endothelial function in pregnancy.