A translational approach to understanding cellular responses to vascular injury

dc.contributor.authorSedovy, Meghanen
dc.contributor.committeechairJohnstone, Scott Roberten
dc.contributor.committeememberLi, Liwuen
dc.contributor.committeememberGourdie, Roberten
dc.contributor.committeememberIsakson, Branten
dc.contributor.committeememberLamouille, Samyen
dc.contributor.departmentGraduate Schoolen
dc.date.accessioned2025-06-04T08:04:04Zen
dc.date.available2025-06-04T08:04:04Zen
dc.date.issued2025-06-03en
dc.description.abstractAppropriate 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.en
dc.description.abstractgeneralWhen large arteries are damaged, such as after a vascular surgery, cells that make up the arterial wall must undergo healing through carefully controlled cell division and migration. If these healing processes go wrong, blockages can form in the artery. Previous research shows that a cell-to-cell communication protein called connexin 43 (Cx43) can control vascular cell division and migration. Because of this, I hypothesized that Cx43 is involved in the cellular response to vascular damage and that changes to this protein could result in vascular disease. To study this, I developed a vascular injury model in mice, then modified the Cx43 protein to understand its role in regulating vascular injury response. I identified that changes made to the Cx43 protein by mitogen activated protein kinase (MAPK) promoted normal wound healing functions in one cell type (endothelial cells), while the same MAPK induced changes induced vascular disease phenotypes in another (smooth muscle cells). Lastly, I showed that targeting Cx43 can limit the development of injury induced human vascular disease.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:43042en
dc.identifier.urihttps://hdl.handle.net/10919/135032en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectVascularen
dc.subjectConnexin 43en
dc.subjectSmooth Muscleen
dc.subjectEndothelialen
dc.subjectNeointimaen
dc.subjectWound Healingen
dc.titleA translational approach to understanding cellular responses to vascular injuryen
dc.typeDissertationen
thesis.degree.disciplineTranslational Biology, Medicine and Healthen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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