Review
Tirzepatide, a dual GIP/GLP-1 receptor agonist, attenuates endothelial dysfunction and angiotensin II-induced abdominal aortic aneurysm in ApoE− /− mice
Alvaro ´ Gomez-Martín ´ a,b, Patrice Marques a,c,d , Cristina Arce-Recatala´ a,b, Angela ´ Vea a,b, Elena Domingo a,b, Blanca Alabadi e,f , Jose ´ T. Real e,f,, María-Jesús Sanz a,b,f,, Laura Piqueras a,b,f,
a Department of Pharmacology, University of Valencia, Valencia, Spain
b Institute of Health Research-INCLIVA, Valencia, Spain
c Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
d CIBEREHD-Spanish Biomedical Research Center in Hepatic and Digestive Diseases, Carlos III Health Institute (ISCIII), Madrid, Spain
e Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Valencia, Spain
f CIBERDEM-Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute (ISCIII), Madrid, Spain
ARTICLE INFO
Edited by Dr G Liu
Keywords:
Abdominal aortic aneurysm
GLP-1 receptor
GIP receptor
Angiotensin-II
Inflammation
Endothelial dysfunction, tirzepatide
Highlights
- Dual GLP-1R/GIPR agonism mitigates endothelial dysfunction and suppresses inflammatory pathways driving AAA progression.
ABSTRACT
Endothelial dysfunction is a critical initiating event in abdominal aortic aneurysm (AAA), a condition posing a high risk of a fatal rupture. Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists have emerged as potent treatments for diabetes and obesity, with clinical evidence suggesting broader cardiovascular benefits. However, the direct impact of tirzepatide (dual GLP-1R/GIPR agonist) on endothelial dysfunction and AAA pathogenesis remains poorly understood. We investigated the ef- fects of dual GLP-1R/GIPR agonism on endothelial dysfunction and AAA development.
We employed parallel-plate flow chamber assays to evaluate the effects of tirzepatide on TNFα-induced leu- kocyte–endothelium interactions. Expression of GLP-1R, GIPR, adhesion molecules (VCAM-1 and ICAM-1), and NF-κB activation was quantified using immunofluorescence and western blotting. The in vivo efficacy of tirze- patide was assessed using an angiotensin-II-infused apoE− /− mouse model of AAA.
GLP-1R and GIPR were expressed in human endothelial cells and murine suprarenal aortas. Tirzepatide significantly attenuated TNFα-induced leukocyte–endothelium interactions, downregulated VCAM-1/ICAM-1/ CX3CL1 expression, and inhibited the mRNA expression and generation of MCP-1 and RANTES. Mechanistically, these effects were driven by the suppression of NF-κB activation. Chronic subcutaneous administration of tir- zepatide over 28 days significantly limited suprarenal aortic expansion and reduced AAA incidence in Ang-II- infused mice. This vasoprotective effect was characterized by preserved elastin integrity, reduced neovessel formation, and diminished macrophage accumulation within the aneurysmal wall.
Dual GLP-1R/GIPR agonism mitigates endothelial dysfunction and suppresses inflammatory pathways driving AAA progression. These findings position tirzepatide as a promising therapeutic strategy for the prevention of vascular remodeling and AAA development.
Article
The pleiotropic effects of tirzepatide – specifically the mitigation of vascular inflammation, pathological neovascularization, and MMP dysregulation – demonstrate that dual receptor activation effectively preserves aortic structural integrity. These findings suggest that therapeutic dual GLP− 1R/GIPR agonism represents a viable clinical strategy to limit AAA progression and its associated mortality.
In conclusion, the present study provides the first evidence that dual GLP− 1R/GIPR agonism significantly reduces endothelial dysfunction and attenuates AAA formation in a murine model.
Available online July 14, 2026
2308-8567/© 2026 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).