title: Role of impaired endothelial cell Ca(2+) signaling in uteroplacental vascular dysfunction during diabetic rat pregnancy.
abstract: Diabetes mellitus in pregnancy is associated with impaired endothelium-mediated dilatation of maternal arteries, although the underlying cellular mechanisms remain unknown. In this study, we hypothesized that diabetes during rat gestation attenuates agonist-induced uterine vasodilation through reduced endothelial cell (EC) Ca(2+) elevations and impaired smooth muscle cell (SMC) hyperpolarization and SMC intracellular Ca(2+) concentration ([Ca(2+)]i) responses. Diabetes was induced by an injection of streptozotocin to second-day pregnant rats and confirmed by the development of maternal hyperglycemia. Control rats were injected with a citrate buffer. Fura-2-based measurements of SMC [Ca(2+)]i or microelectrode recordings of SMC membrane potential were performed concurrently with dilator responses to ACh in uteroplacental arteries from control and diabetic pregnant rats. Basal levels of EC [Ca(2+)]i and ACh-induced EC [Ca(2+)]i elevations in pressurized vessels and small EC sheets were studied as well. Diabetes reduced ACh-induced vasodilation due to a markedly impaired EDHF-mediated response. Diminished vasodilation to ACh was associated with attenuated SMC hyperpolarization and [Ca(2+)]i responses. Basal levels of EC [Ca(2+)]i and ACh-induced EC [Ca(2+)]i elevations were significantly reduced by diabetes. In conclusion, these data demonstrate that reduced endothelium-mediated hyperpolarization contributes to attenuated uteroplacental vasodilation and SMC [Ca(2+)]i responses to ACh in diabetic pregnancy. Impaired endothelial Ca(2+) signaling is in part responsible for endothelial dysfunction in the uterine resistance vasculature of diabetic rats. Pharmacological improvement of EC Ca(2+) handling may provide an important strategy for the restoration of endothelial function and enhancement of maternal blood flow in human pregnancies complicated by diabetes.
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, College of Medicine, University of Vermont, Burlington, VT 05405, USA. Natalia.Gokina@uvm.edu
authors: Natalia I
authors: NI
authors: Gokina
authors: Adrian D
authors: AD
authors: Bonev
authors: Alexander P
authors: AP
authors: Gokin
authors: Gabriela
authors: G
authors: Goloman
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D016640:Diabetes, Gestational / Q000378:metabolism* / Q000503:physiopathology*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology; D010920:Placenta / Q000098:blood supply; D021041:Placental Circulation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D055988:Uterine Artery / Q000378:metabolism / Q000503:physiopathology*; D014599:Uterus / Q000098:blood supply; D014664:Vasodilation
chemical_list: D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D000109:Acetylcholine; D002118:Calcium
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