We aimed to study the role of the ECS in a hypercholesterolemia-induced AS model by establishing an LDLR–CB1R double-KO mouse model, in which we found significant functional vascular remodeling affected by the presence of CB1Rs. Our results indicate that an HFD increased systolic and diastolic BP values in LDLR-KO mice, which was attenuated in HFD-fed CB1R-KO mice compared to an HFD-fed LDLR-KO–CB1R-WT group. The gene discussed is CNR1; the disease is Hypercholesterolemia.