title: Maternal nutrient restriction during pregnancy impairs an endothelium-derived hyperpolarizing factor-like pathway in sheep fetal coronary arteries.
abstract: The mechanisms underlying developmental programming are poorly understood but may be associated with adaptations by the fetus in response to changes in the 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% U.S. National Research Council (NRC)] or nutrient-restricted (60% NRC) diet from days 50 to 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. Large-conductance, calcium-activated potassium channel (BKCa) currents did not differ in coronary smooth muscle cells from control and nutrient-restricted animals. The BKCa openers, BMS 191011 and NS1619, and 14,15-epoxyeicosatrienoic acid [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 a 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 nitric oxide, which may represent an adaptive response to compensate for the absence of the EDHF-like pathway.
authors.affiliation: Department of Pharmaceutical Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota; and.
authors.forename: Praveen
authors.initials: P
authors.lastname: Shukla
authors.affiliation: Department of Pharmaceutical Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota; and.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ghatta
authors.affiliation: Department of Pharmaceutical Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota; and.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Dubey
authors.affiliation: Department of Animal Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota.
authors.forename: Caleb O
authors.initials: CO
authors.lastname: Lemley
authors.affiliation: Department of Animal Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota.
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Johnson
authors.affiliation: Department of Pharmaceutical Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota; and.
authors.forename: Amit
authors.initials: A
authors.lastname: Modgil
authors.affiliation: Department of Animal Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Vonnahme
authors.affiliation: Department of Animal Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Caton
authors.affiliation: Department of Animal Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Reynolds
authors.affiliation: Department of Pharmaceutical Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota; and.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Sciences and Center for Nutrition and Pregnancy, North Dakota State University, Fargo, North Dakota; and stephen.orourke@ndsu.edu.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: O'Rourke
mesh_terms: D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D001920:Bradykinin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005318:Fetal Heart / Q000254:growth & development; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics / Q000378:metabolism; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics / Q000378:metabolism; D044342:Malnutrition / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D039382:Maternal Nutritional Physiological Phenomena; D009569:Nitric Oxide / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D001920:Bradykinin
keywords: BKCa channels; endothelium-derived hyperpolarizing factor; fetal coronary artery; maternal nutrient restriction; nitric oxide