Gap Junction Regulation of Vascular Tone: Implications of Modulatory Intercellular Communication During Gestation

Abstract

In the vasculature, gap junctions (GJ) play a multifaceted role by serving as direct conduits for cell–cell intercellular communication via the facilitated diffusion of signaling molecules. GJs are essential for the control of gene expression and coordinated vascular development in addition to vascular function. The coupling of endothelial cells to each other, as well as with vascular smooth muscle cells via GJs, plays a relevant role in the control of vasomotor tone, tissue perfusion and arterial blood pressure. The regulation of cell-signaling is paramount to cardiovascular adaptations of pregnancy. Pregnancy requires highly developed cell-to-cell coupling, which is affected partly through the formation of intercellular GJs by Cx43, a gap junction protein, within adjacent cell membranes to help facilitate the increase of uterine blood flow (UBF) in order to ensure adequate perfusion for nutrient and oxygen delivery to the placenta and thus the fetus. One mode of communication that plays a critical role in regulating Cx43 is the release of endothelial-derived vasodilators such as prostacyclin (PGI2) and nitric oxide (NO) and their respective signaling mechanisms involving second messengers (cAMP and cGMP, respectively) that are likely to be important in maintaining UBF. Therefore, the assertion we present in this review is that GJs play an integral if not a central role in maintaining UBF by controlling rises in vasodilators (PGI2 and NO) via cyclic nucleotides. In this review, we discuss: (1) GJ structure and regulation; (2) second messenger regulation of GJ phosphorylation and formation; (3) pregnancy-induced changes in cell-signaling; and (4) the role of uterine arterial endothelial GJs during gestation. These topics integrate the current knowledge of this scientific field with interpretations and hypotheses regarding the vascular effects that are mediated by GJs and their relationship with vasodilatory vascular adaptations required for modulating the dramatic physiological rises in uteroplacental perfusion and blood flow observed during normal pregnancy.

Domain-Specific Partitioning of Uterine Artery Endothelial Connexin43 and Caveolin-1

“…Elevations in these endothelial vasodilators are responsible for proportional inductions of the respective elevated levels of cAMP 8,13,19 and cGMP 8,13,19 . Signaling of cyclic nucleotides are further implicated in the formation and assembly of GJs through posttranslational modifications of Cx43 22 . Thus this signaling process involves a feedforward loop between ATP, cyclic nucleotides, and Cx43-mediated GJIC to establish this pregnancy specific vasodilatory phenotype.…”

Uterine perivascular adipose tissue is a novel mediator of uterine artery blood flow and reactivity in rat pregnancy

“…prostacyclin and nitric oxide) (Ampey et al . ). The role of intercellular communication in uterine vascular adaptations to pregnancy has been primarily addressed in the context of endothelial‐to‐endothelial cell and endothelial‐to‐vascular smooth muscle cell interactions (Ampey et al .…”

Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication

“…Few other important EC functions were tested [20]. To help advance efforts to therapeutically rebuild the GCX in a functional manner, we assessed the efficacy of HS regeneration by probing gap junctions, which are of great interest due to their complexity and mediation of many vasculoprotective EC functions [31–33]. Gap junctions in EC are formed by connexin (Cx) proteins of various isoforms.…”