Endothelial GLP-1 (Glucagon-Like Peptide-1) Receptor Mediates Cardiovascular Protection by Liraglutide In Mice With Experimental Arterial Hypertension.

Objective: Cardiovascular outcome trials demonstrated that GLP-1 (glucagon-like peptide-1) analogs including liraglutide reduce the risk of cardiovascular events in type 2 diabetes mellitus. Whether GLP-1 analogs reduce the risk for atherosclerosis independent of glycemic control is challenging to elucidate as the GLP-1R (GLP-1 receptor) is expressed on different cell types, including endothelial and immune cells. Approach and Results: Here, we reveal the cardio- and vasoprotective mechanism of the GLP-1 analog liraglutide at the cellular level in a murine, nondiabetic model of arterial hypertension. Wild-type (C57BL/6J), global ( Glp1r ^-/- ), as well as endothelial ( Glp1r ^f lox/floxxCdh5 ^cre ) and myeloid cell-specific knockout mice ( Glp1r ^flox/flox xLysM ^cre ) of the GLP-1R were studied, and arterial hypertension was induced by angiotensin II. Liraglutide treatment normalized blood pressure, cardiac hypertrophy, vascular fibrosis, endothelial dysfunction, oxidative stress, and vascular inflammation in a GLP-1R-dependent manner. Mechanistically, liraglutide reduced leukocyte rolling on the endothelium and infiltration of myeloid Ly6G ^- Ly6C ⁺ and Ly6G ⁺ Ly6C ⁺ cells into the vascular wall. As a consequence, liraglutide prevented vascular oxidative stress, reduced S-glutathionylation as a marker of eNOS (endothelial NO synthase) uncoupling, and increased NO bioavailability. Importantly, all of these beneficial cardiovascular effects of liraglutide persisted in myeloid cell GLP-1R-deficient ( Glp1r ^flox/flox xLysM ^cre ) mice but were abolished in global ( Glp1r ^-/- ) and endothelial cell-specific ( Glp1r ^flox/flox xCdh5 ^cre ) GLP-1R knockout mice.
Conclusions: GLP-1R activation attenuates cardiovascular complications of arterial hypertension by reduction of vascular inflammation through selective actions requiring the endothelial but not the myeloid cell GLP-1R.