title: Pregnancy attenuates uterine artery pressure-dependent vascular tone: role of PKC/ERK pathway.
abstract: The mechanisms of adaptation of uterine artery vascular tone to pregnancy are not fully understood. The present study tested the hypothesis that pregnancy decreases the PKC-mediated Ca(2+) sensitivity of the contractile process and attenuates myogenic tone in resistance-sized uterine arteries. In pressurized uterine arteries from nonpregnant (NPUA) and near-term pregnant (PUA) sheep, we measured, simultaneously in the same tissue, vascular diameter and vessel wall intracellular Ca(2+) concentration ([Ca(2+)](i)) as a function of intraluminal pressure. In both NPUA and PUA, membrane depolarization with KCl caused a rapid increase in [Ca(2+)](i) and a decrease in diameter. A pressure increase from 20 to 100 mmHg resulted in a transient increase in diameter that was associated with an increase in [Ca(2+)](i), followed by myogenic contractions in the absence of further changes in [Ca(2+)](i). In addition, activation of PKC by phorbol 12,13-dibutyrate induced a decrease in diameter in the absence of changes in [Ca(2+)](i). Pressure-dependent myogenic responses were significantly decreased in PUA compared with NPUA. However, pressure-induced increases in [Ca(2+)](i) were not significantly different between PUA and NPUA. The ratio of changes in diameter to changes in [Ca(2+)](i) was significantly greater for pressure-induced contraction of NPUA than that of PUA. Inhibition of PKC by calphostin C significantly attenuated the pressure-induced vascular tone and eliminated the difference of myogenic responses between NPUA and PUA. In contrast, the MAPKK (MEK) inhibitor PD-098059 had no effect on NPUA but significantly enhanced myogenic responses of PUA. In the presence of PD-098059, there was no difference in pressure-induced myogenic responses between NPUA and PUA. The results suggest that pregnancy downregulates pressure-dependent myogenic tone of the uterine artery, which is partly due to increased MEK/ERK activity and decreased PKC signal pathway leading to a decrease in Ca(2+) sensitivity of myogenic mechanism in the uterine artery during pregnancy.
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA. lzhang@llu.edu
authors.forename: Daliao
authors.initials: D
authors.lastname: Xiao
authors.forename: John N
authors.initials: JN
authors.lastname: Buchholz
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001158:Arteries / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000502:physiology; D009129:Muscle Tonus / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011247:Pregnancy / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology*; D014599:Uterus / Q000098:blood supply*; D014655:Vascular Resistance / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium