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 (PGI(2)). 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 PGI(2) 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 PGI(2) 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 mu M). The stable metabolite of PGI(2), 6-keto-PGF(1 alpha), was measured in culture media and expressed as ng/mg wet wt * 24 h. PGI(2) 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 PGI(2) production in UA. In pPA, 100 ng/mL bFGF induced a 2.2-fold increase (p < 0.01) in PGI(2) 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 PGI(2) 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 PGI(2) production; however, 10, 50, and 100 ng/mL EGF, enhanced (p < 0.03) PGI(2) 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 PGI(2) production, with no recovery after treatment with growth factors,We conclude that PGI(2) 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 PGI(2) secretion is endothelium-derived via de novo synthesis, bFGF, VEGF, and EGF, in addition to angiogenesis, may modulate PGI(2) production, further enhancing blood flow to the growing uteroplacental bed. (C) 1999 Elsevier Science Inc. All rights reserved.