Maternal Nutrient Restriction During Pregnancy Impairs an Endothelium-Derived Hyperpolarizing Factor-Like Pathway in Sheep Fetal Coronary Arteries

Praveen Shukla, Srinivas Ghatta, Nidhi Dubey, Caleb O Lemley, Mary Lynn Johnson, Amit Modgil, Kimberly A. Vonnahme, Joel S. Caton, Lawrence P. Reynolds, Chengwen Sun, Stephen T. O'Rourke


The mechanisms underlying developmental programming are poorly understood but may be associated with adaptations by the fetus in response to changes in maternal environment during pregnancy. We hypothesized that maternal nutrient restriction during pregnancy alters vasodilator responses in fetal coronary arteries. Pregnant ewes were fed a control (100% NRC) or nutrient-restricted (60% NRC) diet from day 50-130 of gestation (term = 145 days); fetal tissues were collected at day 130. In coronary arteries isolated from control fetal lambs, relaxation to bradykinin was unaffected by nitro-l-arginine (NLA). Iberiotoxin or contraction with KCl abolished the NLA-resistant response to bradykinin. In fetal coronary arteries from nutrient-restricted ewes, relaxation to bradykinin was fully suppressed by NLA. BKCa currents did not differ in coronary smooth muscle cells from control and nutrient-restricted animals. The BKCa-openers, BMS191011 and NS1619, and 14,15-EET (a putative endothelium-derived hyperpolarizing factor [EDHF]), each caused fetal coronary artery relaxation and BKCa current activation that was unaffected by maternal nutrient restriction. Expression of BKCa-channel subunits did not differ in fetal coronary arteries from control or undernourished ewes. The results indicate that maternal undernutrition during pregnancy results in loss of the EDHF-like pathway in fetal coronary arteries in response to bradykinin, an effect that cannot be explained by decreased number or activity of BKCa channels, or by decreased sensitivity to mediators that activate BKCa channels in vascular smooth muscle cells. Under these conditions, bradykinin-induced relaxation is completely dependent on NO, which may represent an adaptive response to compensate for the absence of the EDHF-like pathway.

  • maternal nutrient restriction
  • fetal coronary artery
  • nitric oxide
  • endothelium-derived hyperpolarizing factor
  • BKCa channels