Part I: Role of incretin hormones and DPP-IV inhibitors on the control of vascular homeostasis in physiological conditions and their involvement in vascular diseases Part II: Sphingolipid de novo pathway is a novel regulator of vascular homeostasis

The first part of this scientific work has been focused on the role of Dipeptidyl-Peptidase IV (DPP-IV) inhibitors in vascular homeostasis regulation. DPP-IV inhibitors represent a class of antidiabetic drugs. By increasing the physiological levels of incretin hormones, as GLP-1 and GIP, DPP-IV inhibitors sustain the release of insulin and the control of circulating plasma glucose levels. It has been shown that DPP-IV inhibitors are able to improve vascular function independently to their ability in controlling blood glucose levels. Hyperglycemic condition damages endothelium layer with consequent impairment of eNOS/NO-mediated control on vessels homeostasis leading to vascular dysfunction. We demonstrated that Linagliptin, a DPP-IV inhibitor, by interfering with the protein†"protein interaction CAV-1/eNOS, led to an increased eNOS availability, thus enhancing NO production. This mechanism accounts for the beneficial vascular effect of Linagliptin that is independent from glucose control and GLP-1/GLP-1R interaction. In the context of endothelial dysfunction, the second part of this work reveals sphingolipid de novo biosynthesis as a necessary pathway to preserve endothelial cell-dependent regulation of vascular tone and BP homeostasis. Sphingolipids represent important components of plasma membrane as well as bioactive molecules. Sphingolipid de novo biosynthesis tightly regulates the physiological levels of sphingolipids. Serine-Palmitoyl Transferase (SPT) represents the first rate-limiting enzyme of this pathway, and we demonstrated that downregulation of endothelial de novo sphingolipid biosynthesis, by deletion of SPT, increases BP and impairs endothelial cell functions. Thus, endothelial-derived sphingolipids are important in the regulation of endothelial-dependent BP homeostasis. Alterations of their levels below or above a physiological range leads to alteration in vascular tone and BP regulation.