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Review
. 2022 Dec 7;70(1):e220105.
doi: 10.1530/JME-22-0105. Print 2023 Jan 1.

The epidermal growth factor receptor in healthy pregnancy and preeclampsia

Luca Clemente  1 , Ian M Bird  1   2
Affiliations
Review

The epidermal growth factor receptor in healthy pregnancy and preeclampsia

Luca Clemente et al. J Mol Endocrinol. .

Abstract

The epidermal growth factor receptor (EGFR) is expressed robustly in the placenta, and critical processes of pregnancy such as placental growth and trophoblast fusion are dependent on EGFR function. However, the role that aberrant EGFR signaling might play in the etiology and/or maintenance of preeclampsia (PE) remains largely unexplored. Recently, we have shown that overexpression of EGFR in cultured uterine artery endothelial cells (UAEC), which express little endogenous EGFR, remaps responsiveness away from vascular endothelial growth factor receptor (VEGFR) signaling and toward EGFR, suggesting that endothelial EGFR expression may be kept low to preserve VEGFR control of angiogenesis. Here we will consider the evidence for the possibility that the endothelial dysfunction observed in PE might in some cases result from elevation of endothelial EGFR. During pregnancy, trophoblasts are known to synthesize large amounts of EGFR protein, and the placenta regularly releases syncytiotrophoblast-derived exosomes and microparticles into the maternal circulation. Although there are no reports of elevated EGFR gene expression in preeclamptic endothelial cells, the ongoing shedding of placental vesicles into the vascular system raises the possibility that EGFR-rich vesicles might fuse with endothelium, thereby contributing to the symptoms of PE by interrupting angiogenesis and blocking pregnancy-adapted vasodilatory function.

Keywords: EGFR; endothelium; exosome; preeclampsia; pregnancy.

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Conflict of interest statement

Declaration of Competing Interests

There are no conflicts of interest to disclose. Dr Ian Bird is a Senior Editor on the Journal of Endocrinology & Journal of Molecular Endocrinology join editorial board. Dr Ian Bird was not involved in the review or editorial process for this paper, on which he is listed as an author.

Figures

Figure 1
Figure 1. VEGF pretreatment of an endothelial cell monolayer inhibits the ATP-induced Ca2+ burst response.
Pooled passage 4 P-UAEC grown in 35-mm glass-bottom microwell dishes to 95-100% confluence were then loaded with Fura-2 AM, a free Ca2+ dye. Cells were then incubated with 100 μM ATP and the data recorded for 80-100 cells simultaneously for 30 min. After the initial ATP treatment, the dish was washed and allowed to sit for 30 min. Then, VEGF (or another growth factor or cytokine) was added and recorded for 30 min before a subsequent treatment of ATP was added for an additional 30 min. Ca2+ bursts were then counted for the “before” and “after” VEGF treatments. Finally, before and after counts of cell burst numbers were compared (Boeldt et al. 2015). (A) The tracing from a single cell stimulated with AP before (left) or after (right) treatment with VEGF is shown. Note the narrowing of the initial peak and the fewer subsequent peaks of Ca2+ following VEGF treatment, especially in the period 5 to 15 minutes. These findings are consistent with (B), where intact human umbilical vein tissue is loaded with Fura-2 and DAF-2 (to measure free Ca2+ and NO, respectively) and treated with ATP before and after VEGF treatment (Yi et al. 2010). This data shows overall endothelium response, i.e. the mean level of Ca2+ elevated above the baseline and NO production. Before VEGF exposure, Ca2+ and NO responses are robust. Following VEGF treatment, the mean level of free Ca2+ falls more quickly, and NO production is suppressed.
Figure 2
Figure 2. Overexpression of EGFR in P-UAEC suppresses the ability of VEGFR2 to activate Cx43-associated ERK1/2.
(A) VEGF administration (10 ng/mL) triggers the formation of activated VEGFR-2 homodimers, which initiates Src-mediated phosphorylation of Cx43 Y265 and Src-dependent ERK-mediated phosphorylation of Cx43 S279/282, which results in gap junctional gate closure and loss of periodic TRP channel-mediated Ca2+ entry needed for pregnancy-adapted vasodilation. While the exact nature of communication between Cx43 opening and TRPC channel activation remains unclear, pharmacological inhibition of either Src (PP2, 10 μM) or MEK (U0126, 10 μM) protects the sustained Ca2+ burst response from VEGF-induced downregulation. (B) Overexpression of EGFR appears to have significant effects on the local environment at the plasma membrane, as evidenced by the fact that VEGF was not able to inhibit ATP-stimulated Ca2+ bursting in the presence of concentrated EGFR. We proposed that the overexpression of EGFR in P-UAEC localizes the receptor in membrane regions where it is normally absent, thereby conferring access to effector molecules that it would otherwise be denied. The constitutively autophosphorylated C-terminal tail of EGFR serves as a continuous source of active phosphotyrosine docking sites, thereby acting as a sink for effector molecules such as SOS, Grb2, the Ras-GTPase, Raf-1, Shc, Cbl and PLCγ. This effectively reduces their availability for other receptors such as VEGFR2. Of note, EGFR does not prevent VEGF-activated Src phosphorylation of Cx43 Y265, which is known to initiate gap junction disassembly but is apparently not associated with acute gate closure of the gap junction. (C) Normally, treatment of P-UAEC with EGF has no significant effect on gap junctional communication or Ca2+ bursting, presumably due to the low expression level of EGFR. However, when P-UAEC that overexpress EGFR are treated with EGF (10 ng/mL), Src- and ERK-mediated phosphorylations of Cx43 occur and Ca2+ bursting is inhibited. Unlike VEGFR2-mediated Ca2+ burst inhibition, the activation of MAPK pathway by EGFR does not require Src. Only pretreatment with the MEK inhibitor U0126 protects against EGFR-induced gap junctional closure and impaired Ca2+ bursting.
Figure 3
Figure 3. Putative mechanism for EGFR-mediated endothelial cell dysfunction in PE.
(A) Exosomes and microparticles containing a variety of proteins, micro RNAs, etc. are released from the placenta into the uterine and systemic vasculature, some of which may fuse with arterial endothelium. This exosomal fusion is likely to be benign or beneficial. As delivery of exogenous EGFR (and potentially ligands, EGFL7, etc.) increases with time, there may be a limit placed on the ability of VEGFR (yellow) to control endothelial function and particularly late term angiogenesis. (B) In PE pregnancy, where exosomal delivery may further increase, excessive delivery of EGFR and related signaling molecules to the endothelial plasma membrane now overwhelms the VEGFR2 (orange) signaling system completely, rendering the receptor incapable of endothelial cell control. The hypoxia and/or inflammation associated with PE is likely to alter not only EGFR concentration, but signaling adaptors, kinase subtypes, and miRNA co-delivered in the same PE placenta-derived vesicles, reflecting the placenta response to physiologic distress.
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