A translational approach to understanding cellular responses to vascular injury

Abstract

Appropriate control of cell proliferation and migration is essential for maintaining open arteries after vascular injury. Connexin 43 is a channel protein that facilitates cell to cell communication and regulates cell proliferation as well as migration, yet it's role in vascular cell types is poorly understood. Here, I hypothesized that Cx43 and its functional regulation by kinases play a role in vascular cell injury response. To investigate this, I used human vascular tissue from coronary artery bypass grafts and mouse models of ligation induced vascular injury. First, I investigated vessels used for coronary artery bypass, finding damage to the vascular endothelium that could not be completely reversed by improved presurgical vessel storage methods. I developed a carotid artery ligation model of endothelial injury in mice, and found that Cx43 was expressed only in injured endothelial cells, where it promoted healing through control of proliferation and migration. I also identified Mitogen Activated Protein Kinase (MAPK) phosphorylation of Cx43 as the mechanistic event controlling Cx43 dependent endothelial wound healing. In vascular smooth muscle, MAPK dependent Cx43 phosphorylation drove excessive proliferation leading to neointima formation and vascular blockage. A Johnstone lab developed peptide that targets this phosphorylation state prevents neointima formation in mouse and human tissues. These findings highlight a role for Cx43 phosphorylation by MAPK in vascular cell response to mechanical injury and identify Cx43 and a therapeutic target for preventing smooth muscle driven vascular disease.