Dipeptidyl peptidase-4 inhibition and vascular repair by mobilization of endogenous stem cells in diabetes and beyond

- Bone marrow derived cells contribute to cardiovascular homeostasis.
- SDF-1α is a major regulator of vascular stem cell trafficking.
- DPP-4 is a target of anti-diabetic therapy and cleaves SDF-1α.
- DPP-4 regulates vascular stem cell mobilization and response to injury.

Endothelial integrity is maintained by local neighboring cells, but studies in the field of regenerative medicine have highlighted that circulating bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial homeostasis in health and disease. In addition, bone-marrow derived smooth muscle precursors may be recruited to the diseased vasculature. Therefore, modulation of vascular stem/progenitor cells holds promises to tackle the development and progression of vascular disease. The dipeptidyl peptidase-4 (DPP-4) ectopeptidase cleaves several proteins, including the incretin hormones that regulate meal-induced insulin release. Another attractive DPP-4 natural substrate is the highly-conserved chemokine SDF-1α, a major regulator of stem/progenitor cell trafficking in the bone marrow and tissues. DPP-4 might also broadly affect bone marrow function, by acting on hematopoietic growth factors. Emerging data indicate that diabetes is associated with impaired bone marrow structure and function, which translates into pauperization of vascular regenerative cells and contributes to vascular disease. DPP-4 inhibition has potentials to tackle these alteration and promote vascular repair. Currently, millions of diabetic patients around the world are being treated with DPP-4 inhibitors and the study of ancillary effects is gaining an increasing interest for the possible cardiovascular benefit of these drugs beyond glucose control. As DPP-4 inhibitors show favorable safety profiles and do not cause hypoglycemia, they are attractive drugs also for non-diabetic patients and may become part of a vascular regenerative pharmacotherapy.