A potential role for endothelin-1 in human placental growth: interactions with the insulin-like growth factor family of peptides.
Endothelin-1 (Et-1) stimulated DNA synthesis in placental fibroblasts in a dose-dependent manner, as measured by [3H]thymidine incorporation (ED50, 0.2-0.3 ng/mL). Insulin-like growth factor-I (IGF-I) interacted synergistically with Et-1 to potentiate the stimulation of DNA synthesis. Additionally, Et-1 stimulated the turnover of phosphoinositides in a time- and concentration-dependent manner (ED50, 1 ng/mL), as measured by a 2- to 3-fold increase in the total accumulation of [3H]inositol phosphates. This was accompanied by a 2- to 3-fold rise in intracellular calcium, as measured by fura-2 fluorescence. IGF-I, however, had no potentiating effect on Et-1-stimulated phosphoinositide turnover or increase in cytosolic Ca2+. The ability of Et-1 to stimulate the production of IGF-II and IGFBPs by placental fibroblasts was then studied. Western ligand blot analysis using an [125I]IGF-II probe revealed the presence of six major binding proteins corresponding to 42, 38, 35, 32, 31, and 24 kilodaltons. Et-1 (50 ng/mL) stimulated all binding fractions concordantly. This was accompanied by a similar increase in immunoreactive IGF-II secretion, as assessed by a specific RIA. No increase in immunoreactive IGF-I was observed. The ability of the placenta to produce Et-1 was examined by Northern blot analysis. Placentae at 14 and 17 weeks gestation expressed small amounts Et-1 mRNA, whereas significantly higher levels of mRNA were expressed at term. These data suggest that the human placenta produces Et-1 in a developmentally regulated manner that may act via paracrine and/or autocrine mechanisms to regulate placental growth.
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Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235.
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D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D016232:Endothelins / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D010716:Phosphatidylinositols / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis; D017451:Receptors, Somatomedin; D013002:Somatomedins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
D002352:Carrier Proteins; D016232:Endothelins; D018969:Insulin-Like Growth Factor Binding Proteins; D010716:Phosphatidylinositols; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D013002:Somatomedins; D004247:DNA; D002118:Calcium