{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/150188"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/150188","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"Effect of Semaglutide on Vascular Regenerative Cells in People at Elevated Risk for Atherosclerosis","abstract":"Background: Cardiovascular outcome trials demonstrated that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment can reduce major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D) and/or obesity. However, the mechanisms of vascular benefit remain unknown. In particular, the mechanisms of semaglutide, a potently cardio-protective GLP-1RA that can reduce MACE by up to 26%, requires further elucidation from an immune and vascular standpoint. While the effect of semaglutide on reducing key biomarkers of inflammation are well-established, impact on broader immunomodulatory processes such as hematopoieisis remains elusive. The objective of this thesis was to understand the relationship between GLP-1RA therapy and circulating vascular regenerative (VR) progenitor cells with potent pro-angiogenic,vasculogenic and arteriogenic activity. Aims and Methods: We aimed to determine: 1) the correlation between GLP-1RA use and VR cell content in people with T2D through a retrospective analysis of 92 individuals with T2D sub-classified based on ongoing medication use; 2) whether semaglutide administration could increase VR cell content over 6 months through SEMA-VR CardioLink-15, an open-label, randomized controlled trial that compared the effects of usual care (n=24) versus subcutaneous semaglutide (n=22) in adults with T2D and/or obesity; and 3) the effect of semaglutide across a network of immunomodulatory pathways, using an exploratory serum proteomic analysis of 89 circulating proteins measured through Olink®. Results: In individuals with T2D, background use of GLP-1RA (n=22) was associated with greater VR cell content compared to SGLT2i use (n=42) or use of neither therapy (n=30). SEMA-VR CardioLink-15 confirmed this association, demonstrating that 6-month semaglutide led to increased number of circulating VR cells (hematopoietic myeloid and endothelial precursor cells), while reducing pro-inflammatory granulocyte precursors expressing the neutrophil activation marker CD66b and chemokine receptor CXCR2. Olink® serum proteomic analyses revealed semaglutide induced differential expression of 16 proteins involved in cytokine signaling and immune surveillance, corresponding with a downregulation of biological processes involved in pro-inflammatory TNF and interleukin-signaling via NF-kB, while also regulating hematopoietic differentiation pathways. Conclusion: This thesis provides novel insight into the mechanisms of cardiovascular protection mediated by semaglutide through the enhancement of vessel-regenerative progenitor cell content and regulation of inflammatory networks.","abstract_html":"Background: Cardiovascular outcome trials demonstrated that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment can reduce major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D) and/or obesity. However, the mechanisms of vascular benefit remain unknown. In particular, the mechanisms of semaglutide, a potently cardio-protective GLP-1RA that can reduce MACE by up to 26%, requires further elucidation from an immune and vascular standpoint. While the effect of semaglutide on reducing key biomarkers of inflammation are well-established, impact on broader immunomodulatory processes such as hematopoieisis remains elusive. The objective of this thesis was to understand the relationship between GLP-1RA therapy and circulating vascular regenerative (VR) progenitor cells with potent pro-angiogenic,vasculogenic and arteriogenic activity. Aims and Methods: We aimed to determine: 1) the correlation between GLP-1RA use and VR cell content in people with T2D through a retrospective analysis of 92 individuals with T2D sub-classified based on ongoing medication use; 2) whether semaglutide administration could increase VR cell content over 6 months through SEMA-VR CardioLink-15, an open-label, randomized controlled trial that compared the effects of usual care (n=24) versus subcutaneous semaglutide (n=22) in adults with T2D and/or obesity; and 3) the effect of semaglutide across a network of immunomodulatory pathways, using an exploratory serum proteomic analysis of 89 circulating proteins measured through Olink®. Results: In individuals with T2D, background use of GLP-1RA (n=22) was associated with greater VR cell content compared to SGLT2i use (n=42) or use of neither therapy (n=30). SEMA-VR CardioLink-15 confirmed this association, demonstrating that 6-month semaglutide led to increased number of circulating VR cells (hematopoietic myeloid and endothelial precursor cells), while reducing pro-inflammatory granulocyte precursors expressing the neutrophil activation marker CD66b and chemokine receptor CXCR2. Olink® serum proteomic analyses revealed semaglutide induced differential expression of 16 proteins involved in cytokine signaling and immune surveillance, corresponding with a downregulation of biological processes involved in pro-inflammatory TNF and interleukin-signaling via NF-kB, while also regulating hematopoietic differentiation pathways. Conclusion: This thesis provides novel insight into the mechanisms of cardiovascular protection mediated by semaglutide through the enhancement of vessel-regenerative progenitor cell content and regulation of inflammatory networks.","abstract_has_math":false,"creators":["Park, Brady"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Pharmacology","school":null,"contributors":[],"advisors":["Verma, Subodh","Hess, David"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-10","date_published":"2025-10","updated_at":"2026-07-27T21:28:05Z","subjects":["atherosclerosis","endothelial precursor cell","GLP-1 receptor agonists","hematopoietic progenitor cell","semaglutide","vascular regeneration"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1807/150188","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Verma, Subodh","Hess, David"]},{"key":"dc:contributor.department","label":"Department","values":["Pharmacology"]},{"key":"dc:creator","label":"Author","values":["Park, Brady"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-10"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-11-28T17:37:14Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-10"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["atherosclerosis","endothelial precursor cell","GLP-1 receptor agonists","hematopoietic progenitor cell","semaglutide","vascular regeneration"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1807/150188"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Background: Cardiovascular outcome trials demonstrated that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment can reduce major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D) and/or obesity. However, the mechanisms of vascular benefit remain unknown. In particular, the mechanisms of semaglutide, a potently cardio-protective GLP-1RA that can reduce MACE by up to 26%, requires further elucidation from an immune and vascular standpoint. While the effect of semaglutide on reducing key biomarkers of inflammation are well-established, impact on broader immunomodulatory processes such as hematopoieisis remains elusive. The objective of this thesis was to understand the relationship between GLP-1RA therapy and circulating vascular regenerative (VR) progenitor cells with potent pro-angiogenic,vasculogenic and arteriogenic activity. Aims and Methods: We aimed to determine: 1) the correlation between GLP-1RA use and VR cell content in people with T2D through a retrospective analysis of 92 individuals with T2D sub-classified based on ongoing medication use; 2) whether semaglutide administration could increase VR cell content over 6 months through SEMA-VR CardioLink-15, an open-label, randomized controlled trial that compared the effects of usual care (n=24) versus subcutaneous semaglutide (n=22) in adults with T2D and/or obesity; and 3) the effect of semaglutide across a network of immunomodulatory pathways, using an exploratory serum proteomic analysis of 89 circulating proteins measured through Olink®. Results: In individuals with T2D, background use of GLP-1RA (n=22) was associated with greater VR cell content compared to SGLT2i use (n=42) or use of neither therapy (n=30). SEMA-VR CardioLink-15 confirmed this association, demonstrating that 6-month semaglutide led to increased number of circulating VR cells (hematopoietic myeloid and endothelial precursor cells), while reducing pro-inflammatory granulocyte precursors expressing the neutrophil activation marker CD66b and chemokine receptor CXCR2. Olink® serum proteomic analyses revealed semaglutide induced differential expression of 16 proteins involved in cytokine signaling and immune surveillance, corresponding with a downregulation of biological processes involved in pro-inflammatory TNF and interleukin-signaling via NF-kB, while also regulating hematopoietic differentiation pathways. Conclusion: This thesis provides novel insight into the mechanisms of cardiovascular protection mediated by semaglutide through the enhancement of vessel-regenerative progenitor cell content and regulation of inflammatory networks."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Effect of Semaglutide on Vascular Regenerative Cells in People at Elevated Risk for Atherosclerosis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Verma, Subodh","Hess, David"],"dc:contributor.department":["Pharmacology"],"dc:creator":["Park, Brady"],"dc:date":["2025-10"],"dc:date.accessioned":["2025-11-28T17:37:14Z"],"dc:date.issued":["2025-10"],"dc:description.abstract":["Background: Cardiovascular outcome trials demonstrated that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment can reduce major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D) and/or obesity. However, the mechanisms of vascular benefit remain unknown. In particular, the mechanisms of semaglutide, a potently cardio-protective GLP-1RA that can reduce MACE by up to 26%, requires further elucidation from an immune and vascular standpoint. While the effect of semaglutide on reducing key biomarkers of inflammation are well-established, impact on broader immunomodulatory processes such as hematopoieisis remains elusive. The objective of this thesis was to understand the relationship between GLP-1RA therapy and circulating vascular regenerative (VR) progenitor cells with potent pro-angiogenic,vasculogenic and arteriogenic activity. Aims and Methods: We aimed to determine: 1) the correlation between GLP-1RA use and VR cell content in people with T2D through a retrospective analysis of 92 individuals with T2D sub-classified based on ongoing medication use; 2) whether semaglutide administration could increase VR cell content over 6 months through SEMA-VR CardioLink-15, an open-label, randomized controlled trial that compared the effects of usual care (n=24) versus subcutaneous semaglutide (n=22) in adults with T2D and/or obesity; and 3) the effect of semaglutide across a network of immunomodulatory pathways, using an exploratory serum proteomic analysis of 89 circulating proteins measured through Olink®. Results: In individuals with T2D, background use of GLP-1RA (n=22) was associated with greater VR cell content compared to SGLT2i use (n=42) or use of neither therapy (n=30). SEMA-VR CardioLink-15 confirmed this association, demonstrating that 6-month semaglutide led to increased number of circulating VR cells (hematopoietic myeloid and endothelial precursor cells), while reducing pro-inflammatory granulocyte precursors expressing the neutrophil activation marker CD66b and chemokine receptor CXCR2. Olink® serum proteomic analyses revealed semaglutide induced differential expression of 16 proteins involved in cytokine signaling and immune surveillance, corresponding with a downregulation of biological processes involved in pro-inflammatory TNF and interleukin-signaling via NF-kB, while also regulating hematopoietic differentiation pathways. Conclusion: This thesis provides novel insight into the mechanisms of cardiovascular protection mediated by semaglutide through the enhancement of vessel-regenerative progenitor cell content and regulation of inflammatory networks."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["https://hdl.handle.net/1807/150188"],"dc:subject":["atherosclerosis","endothelial precursor cell","GLP-1 receptor agonists","hematopoietic progenitor cell","semaglutide","vascular regeneration"],"dc:title":["Effect of Semaglutide on Vascular Regenerative Cells in People at Elevated Risk for Atherosclerosis"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:28:05Z"}