biostudies-literatureVass ZNational Research and Semmelweis UniversityHungarian National Grants NKFIHHungarian Society of Hypertension, Research Grant 2023Semmelweis University, Faculty of Health Sciences9537https://www.ebi.ac.uk/biostudies/studies/S-EPMC11395437biostudies-literatureUnknown25(17)Hypercholesterolemia forms the background of several cardiovascular pathologies. LDL receptor-knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels and atherosclerosis (AS). Cannabinoid type 1 receptors (CB₁Rs) induce vasodilation, although their role in cardiovascular pathologies is still controversial. We aimed to reveal the effects of CB₁Rs on vascular function and remodeling in hypercholesterolemic AS-prone LDLR-KO mice. Experiments were performed on a newly established LDLR and CB₁R double-knockout (KO) mouse model, in which KO and wild-type (WT) mice were kept on an HFD or a control diet (CD) for 5 months. The vascular functions of abdominal aorta rings were tested with wire myography. The vasorelaxation effects of acetylcholine (Ach, 1 nM-1 µM) were obtained after phenylephrine precontraction, which was repeated with inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX), Nω-nitro-L-arginine (LNA), and indomethacin (INDO), respectively. Blood pressure was measured with the tail-cuff method. Immunostaining of endothelial NOS (eNOS) was carried out. An HFD significantly elevated the cholesterol levels in the LDLR-KO mice more than in the corresponding WT mice (mean values: 1039 ± 162 mg/dL vs. 91 ± 18 mg/dL), and they were not influenced by the presence of the CB₁R gene. However, with the defect of the CB₁R gene, damage to the Ach relaxation ability was moderated. The blood pressure was higher in the LDLR-KO mice compared to their WT counterparts (systolic/diastolic values: 110/84 ± 5.8/6.8 vs. 102/80 ± 3.3/2.5 mmHg), which was significantly elevated with an HFD (118/96 ± 1.9/2 vs. 100/77 ± 3.4/3.1 mmHg, <i>p</i> < 0.05) but attenuated in the CB₁R-KO HFD mice. The expression of eNOS was depressed in the HFD WT mice compared to those on the CD, but it was augmented if CB₁R was knocked out. This newly established double-knockout mouse model provides a tool for studying the involvement of CB₁Rs in the development of hypercholesterolemia and atherosclerosis. Our results indicate that knocking out the CB₁R gene significantly attenuates vascular damage in hypercholesterolemic mice.International journal of molecular sciencesInvestigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein-Cannabinoid Type 1 Receptor Double Knockout Animals.PMC11395437ÚNKP-20-1-SE-12ÚNKP-23-3-II-SE-15PhDKUT0776K132596ÚNKP-22-3-II-SE-6PhDKUT0561K139165K139231Gem JBBanyai BJakus ZNadasy GLKovacs KBTorok VVass ZHorvath EMSzekeres MShenker-Horvath KHunyady LDornyei GVeto KNfalseInvestigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein-Cannabinoid Type 1 Receptor Double Knockout Animals.Hypercholesterolemia forms the background of several cardiovascular pathologies. LDL receptor-knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels and atherosclerosis (AS). Cannabinoid type 1 receptors (CB₁Rs) induce vasodilation, although their role in cardiovascular pathologies is still controversial. We aimed to reveal the effects of CB₁Rs on vascular function and remodeling in hypercholesterolemic AS-prone LDLR-KO mice. Experiments were performed on a newly established LDLR and CB₁R double-knockout (KO) mouse model, in which KO and wild-type (WT) mice were kept on an HFD or a control diet (CD) for 5 months. The vascular functions of abdominal aorta rings were tested with wire myography. The vasorelaxation effects of acetylcholine (Ach, 1 nM-1 µM) were obtained after phenylephrine precontraction, which was repeated with inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX), Nω-nitro-L-arginine (LNA), and indomethacin (INDO), respectively. Blood pressure was measured with the tail-cuff method. Immunostaining of endothelial NOS (eNOS) was carried out. An HFD significantly elevated the cholesterol levels in the LDLR-KO mice more than in the corresponding WT mice (mean values: 1039 ± 162 mg/dL vs. 91 ± 18 mg/dL), and they were not influenced by the presence of the CB₁R gene. However, with the defect of the CB₁R gene, damage to the Ach relaxation ability was moderated. The blood pressure was higher in the LDLR-KO mice compared to their WT counterparts (systolic/diastolic values: 110/84 ± 5.8/6.8 vs. 102/80 ± 3.3/2.5 mmHg), which was significantly elevated with an HFD (118/96 ± 1.9/2 vs. 100/77 ± 3.4/3.1 mmHg, <i>p</i> < 0.05) but attenuated in the CB₁R-KO HFD mice. The expression of eNOS was depressed in the HFD WT mice compared to those on the CD, but it was augmented if CB₁R was knocked out. This newly established double-knockout mouse model provides a tool for studying the involvement of CB₁Rs in the development of hypercholesterolemia and atherosclerosis. Our results indicate that knocking out the CB₁R gene significantly attenuates vascular damage in hypercholesterolemic mice.2024-01-01T00:00:00Z2024 Sep2026-04-26T03:19:52.923Z2025-04-04T02:49:22.174ZS-EPMC113954373927348410.3390/ijms25179537