Effects of angiogenic growth factors on endothelium-derived prostacyclin production by ovine uterine and placental arteries.
Uteroplacental and fetoplacental arteries produce substantial amounts of prostacyclin (PGI2). Because angiogenic growth factors such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) are increased in pregnancy, we hypothesized that treatment of uterine and fetoplacental arteries with bFGF, VEGF, and EGF would further enhance the pregnancy-induced increase in PGI2 production. Duplicate uterine (UA) and fetoplacental (PA) artery (primary branch off of the umbilical cord = pPA; cotyledonary or tertiary = tPA) explants from seven late gestation sheep were placed in tissue culture (RPMI; 37 degrees C) for 24 h alone or with (1-100 ng/mL) bFGF, VEGF, or EGF. To evaluate the endothelial contribution to basal and stimulated PGI2 production and to determine whether it is de novo, arteries with and without endothelium from three additional late gestation ewes, tissues were incubated in the absence or presence of growth factors with or without meclofenamate (1 microM). The stable metabolite of PGI2, 6-keto-PGF1 alpha, was measured in culture media and expressed as ng/mg wet wt 24 h. PGI2 production by UA increased (p < 0.05) from 5.43 +/- 0.26 at control to 8.93 +/- 0.99 with 100 ng/mL bFGF. Although VEGF produced a similar response, EGF did not increase PGI2 production in UA. In pPA, 100 ng/mL bFGF induced a 2.2-fold increase (p < 0.01) in PGI2 production from 1.94 +/- 0.14 to 4.20 +/- 0.31; VEGF and EGF were without effect. In tPA, 50 and 100 ng/mL bFGF increased PGI2 production from 1.98 +/- 0.14 to 3.5 +/- 1.05 and 3.96 +/- 0.46 (p < 0.02). In tPA, VEGF did not increase PGI2 production; however, 10, 50, and 100 ng/mL EGF, enhanced (p < 0.03) PGI2 production from 1.98 +/- 0.14 to 3.39 +/- 0.62, 3.62 +/- 0.26, and 2.93 +/- 0.20. Endothelium removal and meclofenamate treatment caused a 90% and 100% decrease, respectively, in basal PGI2 production, with no recovery after treatment with growth factors. We conclude that PGI2 production is augmented by bFGF in UA, pPA and tPA, by VEGF in UA, and by EGF in tPA during ovine pregnancy. Basal and stimulated PGI2 secretion is endothelium-derived via de novo synthesis. bFGF, VEGF, and EGF, in addition to angiogenesis, may modulate PGI2 production, further enhancing blood flow to the growing uteroplacental bed.
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Department of Obstetrics and Gynecology/Perinatal Research Laboratories, University of Wisconsin-Madison 53715, USA.
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D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D066298:In Vitro Techniques; D008222:Lymphokines / Q000494:pharmacology; D008469:Meclofenamic Acid / Q000494:pharmacology; D010920:Placenta / Q000098:blood supply*; D011247:Pregnancy; D012756:Sheep; D014599:Uterus / Q000098:blood supply*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D006133:Growth Substances; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D008469:Meclofenamic Acid; D004815:Epidermal Growth Factor; D011464:Epoprostenol