Nanofiber Microenvironment Effectively Restores Angiogenic Potential of Diabetic Endothelial Cells

Objective: The effect of chronic hyperglycemic exposure on endothelial cell (EC) phenotype, impaired wound neovascularization, and healing is not completely understood. The hypotheses are: 1) chronic exposure to diabetic conditions in vivo impairs the angiogenic potential of ECs and 2) this deficiency can be improved by an extracellular microenvironment of angiogenic peptide nanofibers. Approach: Angiogenic potential of microvascular ECs isolated from diabetic (db/db) and wild type (wt) mice was assessed by quantifying migration, proliferation, apoptosis, capillary morphogenesis, and vascular endothelial growth factor (VEGF) expression for cell cultures on Matrigel (Millipore, Billerica, MA) or nanofibers under normoglycemic conditions. The in vivo effects of nanofiber treatment on wound vascularization were determined using two mouse models of diabetic wound healing. Results: Diabetic ECs showed significant impairments in migration, VEGF expression, and capillary morphogenesis. The nanofiber microenvironment restored capillary morphogenesis and VEGF expression and significantly increased proliferation and decreased cell apoptosis of diabetic cells versus wt controls. In diabetic wounds, nanofibers significantly enhanced EC infiltration, neovascularization, and VEGF protein levels, as compared to saline treatment; this effect was observed even in MMP9 knockout mice with endothelial progenitor cell (EPC) deficiency. Innovation: The results suggest a novel approach for correcting diabetes-induced endothelial deficiencies via cell interactions with a nanofiber-based provisional matrix in the absence of external angiogenic stimuli. Conclusion: Impaired endothelial angiogenic potential can be restored by angiogenic cell stimulation in the nanofiber microenvironment; this suggests that nanofiber technology for diabetic wound healing and treatment of other diabetes-induced vascular deficiencies is promising.