Semaglutide treatment attenuates vessel remodelling in ApoE−/− mice following vascular injury and blood flow perturbation
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Semaglutide treatment attenuates vessel remodelling in ApoE−/− mice following vascular injury and blood flow perturbation. / Jensen, Ditte Marie; Skovsted, Gry Freja; Bonde, Mathilde Frederikke Bjørn; Bentzon, Jacob Fog; Rolin, Bidda; Franck, Grégrory; Ougaard, Maria Katarina Elm; Voetmann, Louise Marie; Bachmann, Julian Christoffer; Uryga, Anna; Pyke, Charles; Kirk, Rikke Kaae; Hvid, Henning; Knudsen, Lotte Bjerre; Lykkesfeldt, Jens; Nyberg, Michael.
In: Atherosclerosis Plus, Vol. 49, 2022, p. 32-41.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Semaglutide treatment attenuates vessel remodelling in ApoE−/− mice following vascular injury and blood flow perturbation
AU - Jensen, Ditte Marie
AU - Skovsted, Gry Freja
AU - Bonde, Mathilde Frederikke Bjørn
AU - Bentzon, Jacob Fog
AU - Rolin, Bidda
AU - Franck, Grégrory
AU - Ougaard, Maria Katarina Elm
AU - Voetmann, Louise Marie
AU - Bachmann, Julian Christoffer
AU - Uryga, Anna
AU - Pyke, Charles
AU - Kirk, Rikke Kaae
AU - Hvid, Henning
AU - Knudsen, Lotte Bjerre
AU - Lykkesfeldt, Jens
AU - Nyberg, Michael
N1 - Publisher Copyright: © 2022 The Author(s)
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Glucagon-like peptide 1 receptor agonists
KW - Phenotypic switching
KW - Plaque erosion
KW - Semaglutide
KW - Vascular injury
KW - Vascular smooth muscle cells
U2 - 10.1016/j.athplu.2022.05.004
DO - 10.1016/j.athplu.2022.05.004
M3 - Journal article
C2 - 36644202
AN - SCOPUS:85131935970
VL - 49
SP - 32
EP - 41
JO - Atherosclerosis Plus
JF - Atherosclerosis Plus
SN - 2667-0909
ER -
ID: 313496729