Decoding ultimate effects of dipeptidyl peptidase-4 inhibitors on
angiogenesis; an updated comprehensive review of cellular & molecular
mechanisms
Abstract
Angiogenesis is a complex process of new vessel formation on
pre-existing blood vessels. It starts with functional or structural
insult of the endothelium which triggers switch of quiescent endothelial
cells to active angiogenic phenotype. Under physiological conditions,
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 as hypoxia rapidly
disrupt this balanced state eliciting pro-angiogenic switch, and
resulting in unrestricted endothelial proliferation and acceleration of
angiogenesis which are crucial for tumorigenesis and development of
other pathological conditions. Dipeptidyl peptidase-4 (DPP-4) is
cell-surface glycoprotein which serves as serine ectopeptidase. DPP-4
plays a crucial role in the pathophysiological regulation of metabolism,
immune and inflammatory responses, cancer development and cell adhesion
via its catalytic and non-catalytic functions. PPP-4 inhibitors or
gliptins are currently approved anti-hyperglycemic agents for type-2
diabetes mellitus. 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 effects of these drugs on angiogenic processes. In this
review, we will highlight the effects of DPP-4 inhibitors on different
regulatory factors and conditions which control angiogenesis with
specific emphasis on the most recent findings in this regard. Then, we
will explore the underlying reasons and mechanisms behind the
contradictory findings down to a conclusion of the ultimate effects of
DPP-4 inhibitors in angiogenesis during physiological and pathological
states.