Strategies to reverse endothelial progenitor cell dysfunction in diabetes

Abstract

Bone-marrow-derived cells-mediated postnatal vasculogenesis has been reported as the main responsible for the regulation of vascular homeostasis in adults. Since their discovery, endothelial progenitor cells have been depicted as mediators of postnatal vasculogenesis for their peculiar phenotype (partially staminal and partially endothelial), their ability to differentiate in endothelial cell line and to be incorporated into the vessels wall during ischemia/damage. Diabetes mellitus, a condition characterized by cardiovascular disease, nephropathy, and micro- and macroangiopathy, showed a dysfunction of endothelial progenitor cells. Herein, we review the mechanisms involved in diabetes-related dysfunction of endothelial progenitor cells, highlighting how hyperglycemia affects the different steps of endothelial progenitor cells lifetime (i.e., bone marrow mobilization, trafficking into the bloodstream, differentiation in endothelial cells, and homing in damaged tissues/organs). Finally, we review preclinical and clinical strategies that aim to revert diabetes-induced dysfunction of endothelial progenitor cells as a means of finding new strategies to prevent diabetic complications.

Figure 1

Pathways involved in diabetes-induced EPCs toxicity and possible strategies to reverse EPCs damage during bone marrow mobilization. EPCs recruited from bone marrow are here represented. Hyperglycemia alters CXCR-4/SDF-1α pathway, reduces VEGF levels, increases eNOS-mediated production of ROS and a reduction in cleaving enzymes activity. ACE inhibitors and GM-CSF administration improve bone marrow ability to shed EPCs in the periphery. Diabetes-specific metabolic alterations are in red, linked by red arrows to the pathways they interfere with. Red vertical arrows, next to intracellular or extracellular molecules, indicate that their concentration is diminished or increased in diabetic condition compared to nondiabetic status. Drugs with beneficial effect on EPCs are in green, linked by green arrows to the pathways they interact with. MMP-9: matrix metalloproteinase-9; GLO-1: glyoxalase-1; ROS: reactive oxygen species; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; HIF1-α: hypoxia inducible factor 1-α; SDF-1α: stem cell-derived factor-1α; CXCR-4: C-X-C chemokine receptor type 4; VEGF: vascular endothelial growth factor; Kit-L: c-Kit ligand.

Figure 2

Pathways involved in diabetes-induced EPCs toxicity and possible strategies to reverse EPCs damage during trafficking in the peripheral blood. EPCs trafficking in the peripheral blood are here represented. Hyperglycemia, Ox-LDL, and AGEs accumulation induce an impaired migration ability and reduced cell counts by either increased senescence or increased apoptosis of EPCs in both in vivo and in vitro assays. Statins, Adiponectin, CoPP, and MAPK inhibitors are able to reverse diabetes-mediated damage on circulating EPCs. Diabetes-specific metabolic alterations are in red, linked by red arrows to the pathways they interfere with. Red vertical arrows, next to intracellular or extracellular molecules, indicate that their concentration is diminished or increased in diabetic condition compared to nondiabetic status. Drugs with beneficial effect on EPCs are in green, linked by green arrows to the pathways they interact with. ROS: reactive oxygen species; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; VEGF: vascular endothelial growth factor; Ox-LDL: oxidized low-density lipoprotein; MAPK: mitogen-activated protein kinase; CoPP: cobalt protoporphyrin; AGEs: advanced glycation end-products; RAGE: receptor for AGE; PKC: protein kinase C; IL-8: interleukin-8; COX-2: cyclooxygenase-2.

Figure 3

Pathways involved in diabetes-induced EPCs toxicity and possible strategies to reverse EPCs damage during homing. EPCs homing in the sites of ischemia/damage and differentiating into endothelial cells are here represented. Hyperglycemia, Ox-LDL, and AGEs accumulation reduce EPCs adhesion and differentiation ability in both in vivo and in vitro assays. Benfotiamine, an antioxidant molecule, is able to reverse EPCs dysfunction in homing and differentiation. Diabetes-specific metabolic alterations are in red, linked by red arrows to the pathways they interfere with. Red vertical arrows, next to intracellular or extracellular molecules, indicate that their concentration is diminished or increased in diabetic condition compared to nondiabetic status. Drugs with beneficial effect on EPCs are in green, linked by green arrows to the pathways they interact with. MMP-9: matrix metalloproteinase-9; ROS: reactive oxygen species; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; SDF-1α: stem-cell-derived factor-1α; CXCR-4: C-X-C chemokine receptor type 4; Kit-L: c-Kit ligand; Ox-LDL: oxidized low-density lipoprotein; MAPK: mitogen-activated protein kinase; AGEs: advanced glycation end-products; RAGE: receptor for AGE; IL-8: interleukin-8; VEGF: vascular endothelial growth factor.