Matrix Metalloproteinase Enhances Big-Endothelin-1 Constriction in Mesenteric Vessels of Pregnant Rats With Reduced Uterine Blood Flow1

Preeclampsia is a leading cause of maternal and fetal morbidity/ mortality; however, the pathophysiological mechanisms are poorly understood. Vascular endothelial dysfunction in preeclampsia has been partially attributed to changes in endothelin-1 (ET-1). Several enzymes, including matrix metalloproteinases (MMPs, particularly MMP-2), cleave the inactive precursor bigET-1 (bET-1) to active ET-1. Notably, expression levels of MMP-2 have been shown to be increased in women who subsequently develop preeclampsia. We hypothesized that increased MMP-2 expression leads to increased bET-1 conversion, thus increasing vasoconstriction in preeclampsia. A reduced uteroplacental perfusion pressure (RUPP) model of preeclampsia in the rat was used to assess mesenteric artery vascular function. Responses to bET-1 (3–310 nmol/L) and ET-1 (1–200 nmol/L) were studied in the presence or absence of enzyme inhibitors known to cleave bET-1. Vascular contractility in response to bET-1 was greater in RUPP than Sham (P<0.0001), while neither responses to ET-1 nor maximal contractility to high potassium salt solution (KPSS, 123.70 mmol/L) were different. MMP inhibition with GM6001 (30 μmol/L) significantly decreased responses to bET-1 in RUPP (P<0.0001) but not Sham-operated rats. Interestingly, combined treatment with GM6001 and L-NAME (100 μmol/L) revealed a nitric oxide modulation of MMPs that was reduced in RUPP. In summary, we found increased vascular contractility to bET-1 in the RUPP model of preeclampsia that was likely attributable to upstream enzymatic pathways. These data are consistent with a greater contribution of MMP to cleavage of bET-1 to ET-1 ex vivo in RUPP, suggesting that this enzyme may be partially responsible for increased bET-1 induced contractility. The Impact of Malaria in Pregnancy on Changes in Blood Pressure in Children During Their First Year of Life2