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Mol Cell Endocrinol. 2015 Sep 5;412:73-84. doi: 10.1016/j.mce.2015.05.030. Epub 2015 May 29.

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.

Author information

1
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.
2
Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin - Madison, School Medicine and Public Health, Madison, WI 53715, USA.
3
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.
4
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.

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.

KEYWORDS:

CLA; Ca2+; Gap junction; Pregnancy; Src; VEGF

PMID:
26033246
PMCID:
PMC4516676
DOI:
10.1016/j.mce.2015.05.030
[Indexed for MEDLINE]
Free PMC Article
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