Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 412, Issue C, Pages 73-84Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2015.05.030
Keywords
VEGF; Pregnancy; Gap junction; CLA; Src; Ca2+
Categories
Funding
- National Institutes of Health [HL079020, HD38843, HD069181]
- NIH [T32HD41921]
- University of Wisconsin School of Medicine and Public Health Shapiro Award
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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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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