title: Phosphorylation of Ser-279/282 and Tyr-265 positions on Cx43 as possible mediators of VEGF-165 inhibition of pregnancy-adapted Ca2+ burst function in ovine uterine artery endothelial cells.
abstract: Normal pregnancy requires increased uterine endothelial cell driven vasodilation that is related to increases in sustained Ca2+ signaling via increased connexin 43 (Cx43) gap junction function. Preeclampsia, a hypertensive disorder of pregnancy associated with endothelial dysfunction, is also linked with down regulation of Ca2+ driven vasodilator production and increased levels of vascular endothelial growth factor (VEGF). Cx43 function can be acutely down-regulated by phosphorylation of multiple inhibitory residues and VEGF is known to promote phosphorylation of Cx43. Herein, we show that VEGF-165 promotes Cx43 phosphorylation at Ser-279/282 and Tyr-265 residues and blocks pregnancy-adapted Ca2+ signaling in ovine uterine artery endothelial cells (UAEC). Pharmacological Src and ERK kinase pathway inhibitors (PP2 and U0126) reverse these phosphorylations and rescue Ca2+ signaling. We also report a nutraceutical Src inhibitor, t10,c12 conjugated linoleic acid (10,12 CLA), rescues Ca2+ signaling in UAEC and therefore may have therapeutic potential for preeclampsia.
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin - Madison, School Medicine and Public Health, Madison, WI 53715, USA. Electronic address: dsboeldt@wisc.edu.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Boeldt
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin - Madison, School Medicine and Public Health, Madison, WI 53715, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Grummer
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin - Madison, School Medicine and Public Health, Madison, WI 53715, USA.
authors.forename: FuXian
authors.initials: F
authors.lastname: Yi
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin - Madison, School Medicine and Public Health, Madison, WI 53715, USA; Department of Pediatrics, University of Wisconsin - Madison, School Medicine and Public Health, Madison, WI 53715, USA; Department of Animal Sciences, University of Wisconsin - Madison, WI 53715, USA.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Magness
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin - Madison, School Medicine and Public Health, Madison, WI 53715, USA; Department of Pediatrics, University of Wisconsin - Madison, School Medicine and Public Health, Madison, WI 53715, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bird
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D011225:Pre-Eclampsia / Q000378:metabolism; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D012694:Serine / Q000378:metabolism; D034561:Sheep, Domestic; D014443:Tyrosine / Q000378:metabolism; D055988:Uterine Artery / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018031:Connexin 43; D042461:Vascular Endothelial Growth Factor A; D014443:Tyrosine; D012694:Serine; D000255:Adenosine Triphosphate; D019061:src-Family Kinases
keywords: CLA; Ca2+; Gap junction; Pregnancy; Src; VEGF