Adenoviral transduction of EGFR into pregnancy-adapted uterine artery endothelial cells remaps growth factor induction of endothelial dysfunction

Luca Clemente, Derek S. Boeldt, Mary A. Grummer, Mayu Morita, Terry K. Morgan, Greg J. Wiepz, Paul J. Bertics, Ian M. Bird

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

During pregnancy, uterine vascular vasodilation is enhanced through adapted Ca2+ signaling, facilitated through increased endothelial connexin 43 (Cx43) gap junctional communication (GJC). In preeclampsia (PE), this adaptive response is missing. Of note, the angiogenic factor VEGF can also act via Src and ERK to close Cx43 gap junctions. While VEGFR2 is necessary for such closure, a role VEGFR1 is less clear. We reasoned if VEGFR2 is acting alone, then substituting another growth factor receptor with VEGFR2-like signaling should have the same effect. In uterine artery endothelial cells derived from pregnant sheep (P-UAEC), endogenous EGFR expression is very low. When we used adenovirus to raise EGFR, we also dose-dependently induced EGF-sensitive Cx43 phosphorylation mainly via ERK, and corresponding loss of Ca2+ bursts, but eliminated VEGF effects on phosphorylation of Cx43 or loss of Ca2+ bursting. This surprising observation suggests that while activated EGFR may indeed substitute for VEGFR2, it also sequesters a limited pool of effector molecules needed for VEGFR2 to phosphorylate Cx43. Thus, low endogenous EGFR expression in P-UAEC may be a necessary strategy to allow VEGFR-2 control of GJC, a first step in initiating angiogenesis in healthy pregnancy. Of further note, trophoblasts are rich in EGFR, and we have demonstrated shed PLAP+/EGFR + extracellular vesicles in maternal circulation in first trimester plasma samples using nanoscale high resolution flow cytometry. Collectively our data suggest that placenta derived exosomes positive for EGFR should be further considered as a possible cause of endothelial dysfunction in women with PE.

Original languageEnglish (US)
Article number110590
JournalMolecular and Cellular Endocrinology
Volume499
DOIs
StatePublished - Jan 1 2020

Keywords

  • Ca2+
  • EGF
  • EGFR
  • Endothelium
  • ERK
  • Exosome
  • Gap junction
  • Preeclampsia
  • Pregnancy
  • Src
  • VEGF

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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