Effects of the glucagon like-peptide-1 (GLP-1) receptor on vascular function, inflammation and thrombocyte reactivity in angiotensin-II induced arterial hypertension

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Cardiovascular disease are a leading cause of death worldwide. Within the last decades research identified several classical risk factors, like smoking, obesity and arterial hypertension. Arterial hypertension and endothelial function build a close relationship. A normal vascular endothelium releases nitric oxide (NO) by the endothelial NO synthase (eNOS), which acts as a vasodilator and has inhibitory effects on thrombocytes. Endothelial dysfunction was shown to be an indicator for future cardiovascular events in humans and is associated with reduced NO bioavailability. On the one hand the latter relies on a dysfunctional eNOS (uncoupling of the enzyme) and on the other hand increased oxidative stress, which represents a sink for NO. Arterial hypertension is known to be a chronic inflammatory disease, in which infiltration of inflammatory cells (myelomonocytic cells) into the vascular wall plays a major role. This phenomenon is triggered by a dysfunctional (activated) endothelium and further increases vascular oxidative stress resulting in a vicious circle. Besides inflammatory cells, also thrombocytes contribute to endothelial dysfunction. It has been shown, that thrombocytes are hyper-reactive and generate more thrombin in animal models of arterial hypertension.Glucagon like-peptide-1 (GLP-1) is a peptide hormone with known anti-inflammatory properties. It increases insulin release from beta-cells in the pancreas and its synthetic analogs are used for treatment of type 2 diabetes. In a previous work of our group it was shown that GLP-1 improves survival of animals with septic shock, which was accompanied by improved vascular function as well as suppressed oxidative stress and inflammation. Furthermore, our studies demonstrated that GLP-1 has inhibitory effects on inflammatory cells (myelomonocytes) and thrombocytes in experimental sepsis. In preliminary experiments we could demonstrate that vascular inflammation and oxidative stress were reduced, endothelial function was improved in an animal model of arterial hypertension. The aim of the present study is to investigate beneficial effects of GLP-1 on vascular function, oxidative stress, inflammation and thrombocyte reactivity in models of arterial hypertension. In order to obtain more mechanistic insight, cell-specific knockout mice for GLP-1 receptor in endothelial cells, myelomonocytes and thrombocytes will be used. The present study includes a translational approach, in which GLP-1 signaling and endothelial function of patients with arterial hypertension will be investigated.