Vascular Biology of Glucagon Receptor Superfamily Peptides: Mechanistic and Clinical Relevance

Regulatory peptides produced in islet and gut endocrine cells, including glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and glucose-dependent insulinotropic polypeptide, exert actions with considerable metabolic importance and translational relevance. Although the clinical development of GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors has fostered research into how these hormones act on the normal and diseased heart, less is known about the actions of these peptides on blood vessels. Here we review the effects of these peptide hormones on normal blood vessels and highlight their vascular actions in the setting of experimental and clinical vascular injury. The cellular localization and signal transduction properties of the receptors for glucagon, GLP-1, GLP-2, and glucose-dependent insulinotropic polypeptide are discussed, with emphasis on endothelial cells and vascular smooth muscle cells. The actions of these peptides on the control of blood flow, blood pressure, angiogenesis, atherosclerosis, and vascular inflammation are reviewed with a focus on elucidating direct and indirect mechanisms of action. How these peptides traverse the blood-brain barrier is highlighted, with relevance to the use of GLP-1 receptor agonists to treat obesity and neurodegenerative disorders. Wherever possible, we compare actions identified in cell lines and primary cell culture with data from preclinical studies and, when available, results of human investigation, including studies in subjects with diabetes, obesity, and cardiovascular disease. Throughout the review, we discuss pitfalls, limitations, and challenges of the existing literature and highlight areas of controversy and uncertainty. The increasing use of peptide-based therapies for the treatment of diabetes and obesity underscores the importance of understanding the vascular biology of peptide hormone action.