Bizarre expression of tissue inhibitor of metalloproteinase-3 in feto–maternal interface caused gestational hypertension in mice model

Abstract

Department of Obstetrics and Gynaecololgy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Preeclampsia (PE) is believed to result from abnormal placentation in early pregnancy. Shallow endovascular cytotrophoblast invasion and endothelial cell dysfunction are two key features in the pathogenesis of PE. Matrix metalloproteinase-9 (MMP-9) is crucial for the invasive ability of trophoblast cells during placentation. Tissue inhibitor of metalloproteinase-3 (TIMP-3), which is known as a potent inhibitor of MMP-9, also plays a role in regulating trophoblast invasion to the uterine endometrium. However little is known about the role of matrix metalloproteases and their inhibitors on regulation of maternal and fetal circulation. In the present study, we applied in vivo gene transfer system with hemagglutinating virus of Japan envelope (HVJ-E) vector into feto–maternal interface of pregnant mice on day 6.5 post coitus (pc), during the period of placental development. Overexpression of TIMP3 cDNA suppressedMMP-9 activity in the uterus. Maternal systolic blood pressure significantly rose from day 14.5 pc to parturition. The fetus and the placentae were significantly smaller, and serum soluble fms-like tyrosine kinase (Flt)-1 and soluble endoglin levelswere significantlyhigher after TIMP-3 treatment than in control mice. These data suggest that the balance between matrix metalloprotease and its inhibitor may play a pivotal role in determining feto/maternal circulation.