Dual Role of Dipeptidyl Peptidase IV (DPP IV) in Angiogenesis and Vascular Remodeling

Our studies, both in vivo and in vitro, strongly indicate a critical role of DPP IV in modifying NPY’s actions in the cardiovascular system. The protein can act as an NPY converting enzyme, cleaving the full length NPY1–36 to its shorter form, NPY3–36, and shifting the peptide’s activities from Y1-mediated vasoconstriction and vascular smooth muscle cell growth to Y2/Y5-mediated angiogenesis. On the other hand, the intriguing phenomenon of DPP IV being a necessary factor in Y1/Y5-mediated vascular smooth muscle cell proliferation implicates its possible role as a co-receptor facilitating signalling of and/or ligand binding to NPY receptors. Additional studies are required to determine mechanisms of DPP IV actions in certain cellular models, e.g. why does the enzyme not inactivate NPY1–36 in the vascular smooth muscle cell-Y1/Y5 system by cleavage of the peptide, or whether or not other proteases, such as aminopeptidase P, can compensate for loss of DPP IV. If DPP IV proves to be indeed a critical step required for inhibiting NPY’s contractile and pro-atherosclerotic effect and potentiating its angiogenic activities, abnormally low DPP IV expression and activity could be a risk factor for hypertension and ischemic cardiovascular diseases, in which NPY has already been implicated28. Research into this area seems particularly necessary as DPP IV inhibitors are being considered as a potential therapy for type II diabetes — a disease, which by itself increases the risk for cardiovascular consequences.