The MMP2 and MMP9-Specific Inhibitor SB-3CT Significantly Decreases Blood Pressure in Pre-eclampsia Model Rats.

Abstract

Although uterine matrix metalloproteinases (MMPs) are known to play a role in the development of pre-eclampsia (PE), it remains unclear whether increased levels of serum MMPs are the pathogenesis underlying pregnancy-induced hypertension (PIH). We aimed to investigate whether the serum levels of MMP2 and MMP9 play a role in PIH using a specific inhibitor, SB-3CT. Twenty-five nine-week-old pregnant rats were randomly divided into five groups: normal pregnancy (SHAM) group, PE (RUPP) group, as well as low, middle, and high-dose intervention groups. The intervention groups received continuous intraperitoneal injections of SB-3CT at 25 mg, 50 mg, or 75 mg/kg/d doses. The SHAM and RUPP groups were injected with equal doses of solvent. Seven days later, the arterial pressure was tested at the carotid artery and rats were sacrificed. Serum MMP2, MMP9, tissue inhibitor of metalloproteinase-1 (TIMP1), endothelin-1 (ET-1), angiotensin II (AngII), and endothelial nitric oxide synthase (eNOS) levels were tested by ELISA. Vascular wall changes in cross-sections of the aorta abdominalis were observed using H&E-staining and the activities of MMP2 and MMP9 in the aorta abdominalis were tested using gelatin zymography. There were significant increases in blood pressure, serum MMP2 and MMP9 levels, and activities of MMP2 and MMP9 in the aorta abdominalis, along with notable vascular remodeling in the RUPP group. After the SB-3CT intervention, increased blood pressure was relieved and vascular remodeling improved, while MMP2 and MMP9 levels and activities were reduced. In summary, specific inhibition of MMP2 and MMP9 can decrease blood pressure in a PIH model. This indicates that increased MMP2 and MMP9 in maternal serum might contribute to the pathogenesis of PIH.