{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/135032"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/135032","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Sedovy, Meghan"],"institution":"Virginia Tech","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Translational Biology, Medicine and Health","degree_department":"Graduate School","school":null,"contributors":[],"advisors":[],"committee_chairs":["Johnstone, Scott Robert"],"committee_members":["Li, Liwu","Gourdie, Robert G.","Isakson, Brant","Lamouille, Samy"],"year":2025,"date_issued":"2025-06-03","date_published":"2025-06-03","updated_at":"2026-07-22T22:18:53Z","subjects":["Vascular","Connexin 43","Smooth Muscle","Endothelial","Neointima","Wound Healing"],"languages":["en"],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:43042"],"render_values":[{"text":"vt_gsexam:43042","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/10919/135032","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Johnstone, Scott Robert"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Li, Liwu","Gourdie, Robert G.","Isakson, Brant","Lamouille, Samy"]},{"key":"dc:contributor.department","label":"Department","values":["Graduate School"]},{"key":"dc:creator","label":"Author","values":["Sedovy, Meghan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-06-04T08:04:04Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2025-06-04T08:04:04Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-06-03"]},{"key":"dc:publisher","label":"Institution","values":["Virginia Tech"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Translational Biology, Medicine and Health"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Virginia Polytechnic Institute and State University"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Vascular","Connexin 43","Smooth Muscle","Endothelial","Neointima","Wound Healing"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://rightsstatements.org/vocab/InC/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:43042"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10919/135032"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:description.abstractgeneral","label":"General Abstract","values":["When 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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["ETD"]},{"key":"dc:title","label":"Title","values":["A translational approach to understanding cellular responses to vascular injury"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Johnstone, Scott Robert"],"dc:contributor.committeemember":["Li, Liwu","Gourdie, Robert G.","Isakson, Brant","Lamouille, Samy"],"dc:contributor.department":["Graduate School"],"dc:creator":["Sedovy, Meghan"],"dc:date.accessioned":["2025-06-04T08:04:04Z"],"dc:date.available":["2025-06-04T08:04:04Z"],"dc:date.issued":["2025-06-03"],"dc:description.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."],"dc:description.abstractgeneral":["When 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."],"dc:description.degree":["Doctor of Philosophy"],"dc:format.medium":["ETD"],"dc:identifier.other":["vt_gsexam:43042"],"dc:identifier.uri":["https://hdl.handle.net/10919/135032"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["Vascular","Connexin 43","Smooth Muscle","Endothelial","Neointima","Wound Healing"],"dc:title":["A translational approach to understanding cellular responses to vascular injury"],"dc:type":["Dissertation"],"thesis:degree_discipline":["Translational Biology, Medicine and Health"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:18:53Z"}