Semaglutide treatment attenuates vessel remodelling in ApoE-/- mice following vascular injury and blood flow perturbation

Ditte Marie Jensen; Gry Freja Skovsted; Mathilde Frederikke Bjørn Bonde; Jacob Fog Bentzon; Bidda Rolin; Grégory Franck; Maria Katarina Elm Ougaard; Louise Marie Voetmann; Julian Christoffer Bachmann; Anna Uryga; Charles Pyke; Rikke Kaae Kirk; Henning Hvid; Lotte Bjerre Knudsen; Jens Lykkesfeldt; Michael Nyberg

doi:10.1016/j.athplu.2022.05.004

Semaglutide treatment attenuates vessel remodelling in ApoE-/- mice following vascular injury and blood flow perturbation

Atheroscler Plus. 2022 Jun 4:49:32-41. doi: 10.1016/j.athplu.2022.05.004. eCollection 2022 Aug.

Authors

Ditte Marie Jensen^{1

2}, Gry Freja Skovsted¹, Mathilde Frederikke Bjørn Bonde², Jacob Fog Bentzon^{3

4}, Bidda Rolin², Grégory Franck⁵, Maria Katarina Elm Ougaard², Louise Marie Voetmann², Julian Christoffer Bachmann², Anna Uryga², Charles Pyke², Rikke Kaae Kirk², Henning Hvid², Lotte Bjerre Knudsen², Jens Lykkesfeldt¹, Michael Nyberg²

Affiliations

¹ Department of Veterinary and Animal Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Copenhagen, Denmark.
² Research and Early Development, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Maaloev, Denmark.
³ Department of Clinical Medicine, Heart Diseases and Steno Diabetes Center Aarhus, Palle Juul-Jensens Boulevard 99, Aarhus University, 8200, Aarhus, Denmark.
⁴ Centro Nacional de Investigaciones Cardiovasculares (CNIC), Alle Melchor Fernandez Almagro, 3, 28029, Madrid, Spain.
⁵ INSERM U1148, Laboratory for Vascular Translational Science, Bichat Hospital, 46 Rue Henri Huchard, Paris, France.

Abstract

Background and aims: Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque.

Methods: In study A, we employed an electrical current to the carotid artery in ApoE-/- mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks. In study B, a constrictive cuff was added for 6 h at the site of the healed segment to induce a disturbance in blood flow.

Results: Compared to vehicle, semaglutide treatment reduced the intimal and medial area by ∼66% (p = 0.007) and ∼11% (p = 0.0002), respectively. Following cuff placement, expression of the pro-inflammatory marker osteopontin and macrophage marker Mac-2 was reduced (p < 0.05) in the semaglutide-treated group compared to vehicle. GLP-1R were not expressed in murine carotid artery and human coronary vessels with and without atherosclerotic plaques, and semaglutide treatment did not affect proliferation of cultured primary human VSMCs.

Conclusions: Semaglutide treatment reduced vessel remodelling following electrical injury and blood flow perturbation in an atheroprone mouse model. This effect appears to be driven by anti-inflammatory and -proliferative mechanisms independent of GLP-1 receptor-mediated signalling in the resident vascular cells. This mechanism of action may be important for cardiovascular protection.

Keywords: ApoE−/−, Apolipoprotein E knock-out; Atherosclerosis; GLP 1RA, Glucagon-like peptide 1 receptor agonist; Glucagon-like peptide 1 receptor agonists; IHC, Immunohistochemistry; ISH, In situ hybridisation; LCCA, Left common carotid artery; Phenotypic switching; Plaque erosion; SSP1, Osteopontin; Semaglutide; SoC, Standard of care; VSMC, Vascular smooth muscle cells; Vascular injury; Vascular smooth muscle cells.