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.