Decoding the Ultimate Effects of Dipeptidyl Peptidase‐4 Inhibitors on Angiogenesis: An Updated Comprehensive Review of the Cellular and Molecular Mechanisms

Abstract

Abstract Angiogenesis is a complex process of forming new blood vessels from pre‐existing ones. It starts with a functional or structural insult of the endothelium, which triggers a switch of quiescent endothelial cells to an active angiogenic phenotype. Physiologically, angiogenesis is limited in time and proliferative power of endothelial cells owing to the finely tuned balance between pro‐angiogenic and anti‐angiogenic programs. Stressful conditions, rapidly disrupt this balanced state, eliciting a pro‐angiogenic switch and resulting in unrestricted endothelial proliferation and acceleration of angiogenesis, which are crucial for tumorigenesis and the development of other pathological conditions. Dipeptidyl peptidase‐4 (DPP‐4), a cell‐surface glycoprotein that serves as a serine ectopeptidase, plays a crucial role in several pathophysiological activities via catalytic and non‐catalytic functions. DPP‐4 inhibitors or gliptins are antidiabetic drugs. Pre‐clinical studies and clinical experience have clearly acknowledged the organ‐protective pleiotropic effects of DPP‐4 inhibitors. Still, the literature shows conflicting results regarding the potential angiogenic effects of these drugs. This review highlights the effects of DPP‐4 inhibitors on different regulatory factors and conditions that control angiogenesis, explores the underlying reasons and mechanisms behind the contradictory findings, and provides a conclusive perspective on the ultimate effects of DPP‐4 inhibitors in angiogenesis during physiological and pathological states.