Injury-induced connexin 43 expression regulates endothelial wound healing

Area of Science:

• Vascular Biology
• Cellular Signaling
• Wound Healing

Background:

• Endothelial cell (EC) injury contributes to vascular surgical failure.
• The role of connexin 43 (Cx43) gap junctions in EC healing is unknown.
• Cx43 is implicated in skin wound healing.

Purpose of the Study:

• To investigate the role of Cx43 in EC healing after vascular injury.
• To determine if Cx43 upregulation is induced by EC injury.
• To elucidate the mechanisms by which Cx43 influences EC migration and proliferation.

Main Methods:

• Secondary analysis of RNA-seq data from injured mouse aortas.
• Development of a novel mouse carotid artery ligation model for EC injury.
• Inducible EC-specific Cx43 knockout (KO) mouse model.
• Single-cell RNA-seq analysis of injured wild-type (WT) and EC-Cx43 KO carotids.
• Analysis of Cx43 phosphorylation mutants in EC healing.

Main Results:

• Cx43 was significantly upregulated in ECs postinjury.
• EC healing was significantly delayed in EC-Cx43 KO mice.
• Single-cell RNA-seq revealed reduced enrichment of migration, proliferation, and ERK/MAPK pathways in Cx43-deficient ECs.
• Cx43 phosphorylation mutants exhibited reduced healing rates similar to KO mice.

Conclusions:

• Mechanical injury to endothelium induces Cx43 expression.
• Cx43 gap junction communication is required for EC migration during vascular wound healing.
• Cx43 phosphorylation is critical for its function in EC healing.