Effect of Semaglutide on Vascular Regenerative Cells in People at Elevated Risk for Atherosclerosis

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.

Department dc:contributor.department

Pharmacology

Year dc:date.issued

2025

Author dc:creator

• Park, Brady

Advisors dc:contributor.advisor

• Verma, Subodh
• Hess, David

• atherosclerosis
• endothelial precursor cell
• GLP-1 receptor agonists
• hematopoietic progenitor cell
• semaglutide
• vascular regeneration

Handle dc:identifier.uri

https://hdl.handle.net/1807/150188

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/150188