Roles of leptin and the leptin receptor in placental endocrinology and angiogenesis during primate pregnancy.

摘要

Leptin, the product of the LEP gene, may play an important role in pregnancy, specifically in the regulation of placental endocrinology and angiogenesis. In trophoblasts collected early in gestation, leptin increases hormone biosynthesis and metalloproteinase secretion and activation, suggesting leptin's involvement in placental function and development. Therefore, we hypothesize that: (1) estrogen regulates the expression of the leptin receptor in the placental syncytiotrophoblast and leptin, in turn, modulates the secretion of human chorionic gonadotropin (hCG), human growth hormone (hGH), and progesterone; (2) leptin, in combination with factors previously known to modulate placental angiogenesis and vascular permeability, regulates placentation by enhancing vascular endothelial cell proliferation.;Studies in the baboon (Papio sp) demonstrated leptin receptor (Ob-R) expression. Furthermore, use of in situ hybridization demonstrated the localization of two leptin receptor isoforms to the leptin-producing, placental syncytiotrophoblast, suggesting the possibility for autocrine/paracrine action. Subsequently, leptin's effect upon placental endocrinology was assessed in vitro using third trimester human syncytiotrophoblast cultures. Leptin did not affect hCG, progesterone or hGH elaboration, and estrogen administration had no effect on leptin secretion or Ob-R transcript abundance in this cell type. Collectively, these results differed from studies using first trimester cells, suggesting that leptin's role(s) in early pregnancy differs from that in late gestation. Leptin may potentially play roles in processes that are pertinent in early pregnancy such as angiogenesis and implantation.;After validating leptin's angiogenic potential using a murine corneal pocket model assay, cultured human umbilical vein endothelial cells (HUVECs) were utilized to test whether leptin affected HUVEC proliferation induced by angiogenic factors pertinent to placentation. Despite Ob-R expression on the cell membrane of HUVECs, leptin did not stimulate cell proliferation. Vascular endothelial growth factor, basic fibroblast growth factor, and tumor necrosis factor alpha induced HUVEC proliferation, but leptin failed to enhance or decrease the effects of any of these factors. These results indicate that the angiogenic effects of leptin may be mediated by a mechanism other than the induction of vascular endothelial cell proliferation. Overall, early in gestation, leptin may mediate placental endocrinology and angiogenesis, a role that may change later in pregnancy.