Unique regulation of human placenta growth factor regulation and expression.

摘要

Angiogenesis has been shown to be critical for placentation, normal growth and development of the fetus [1--4]. Successful pregnancy requires intense vascular growth and remodeling in the placenta and endometrium to establish a competent maternal/fetal interface. Vascular abnormalities contribute to many significant obstetrical complications including preeclampsia, intra-uterine growth retardation (IUGR) and recurrent spontaneous abortions (RSA) [5]. Despite this clinical importance, little is known about the growth factors that regulate placental angiogenesis. Placenta growth factor (PIGF), a member of the vascular endothelial growth factor (VEGF) family, is predominantly expressed by trophoblast in the placenta under normal physiological conditions [6--8]. Non-trophoblast cells express low amounts of PIGF under normal physiological conditions. In the first part of this dissertation we determine promoter regions of the PIGF gene responsible for high constitutive trophoblast specific expression. Our data suggest the presence of a 131 bp trophoblast specific region within the PIGF promoter that up regulates PIGF expression in trophoblast cells while inhibiting PIGF expression in non-trophoblast cells.;PIGF possesses potent angiogenic activity [9] and protects trophoblast from apoptosis. Placental ischemia and subsequent maternal endothelial cell damage and trophoblast apoptosis are hallmark features of preeclampsia, the leading cause of maternal and fetal morbidity and mortality in developed countries. Maternal serum PIGF protein levels are significantly decreased in women diagnosed with preeclampsia [10, 11] compared to normal pregnant women. Trophoblast PIGF expression is down regulated by hypoxia [2, 12, 13]. Thus, in the second part of this dissertation, we determine the mechanism of PIGF down regulation in hypoxic trophoblast. In hypoxic trophoblast there is increased nitric oxide synthase (NOS) production leading to increased endogenous nitric oxide (NO) generation. Our data suggests that this increased endogenous NO inhibits hypoxia inducible factor-1 (HIF-1) DNA-binding ability, and causes down regulation of PIGF expression in hypoxic trophoblast.;This dissertation identifies the minimal functional promoter of the human PIGF gene responsible for high constitutive trophoblast specific expression. We have determined some of the molecules responsible for the unique down regulation of PIGF expression in hypoxic trophoblast. These are some of the key findings in the field of PIGF expression and regulation.