title: Angiogenic microenvironment augments impaired endothelial responses under diabetic conditions.
abstract: Diabetes-induced cardiomyopathy is characterized by cardiac remodeling, fibrosis, and endothelial dysfunction, with no treatment options currently available. Hyperglycemic memory by endothelial cells may play the key role in microvascular complications in diabetes, providing a potential target for therapeutic approaches. This study tested the hypothesis that a proangiogenic environment can augment diabetes-induced deficiencies in endothelial cell angiogenic and biomechanical responses. Endothelial responses were quantified for two models of diabetic conditions: 1) an in vitro acute and chronic hyperglycemia where normal cardiac endothelial cells were exposed to high-glucose media, and 2) an in vivo chronic diabetes model where the cells were isolated from rats with type I streptozotocin-induced diabetes. Capillary morphogenesis, VEGF and nitric oxide expression, cell morphology, orientation, proliferation, and apoptosis were determined for cells cultured on Matrigel or proangiogenic nanofiber hydrogel. The effects of biomechanical stimulation were assessed following cell exposure to uniaxial strain. The results demonstrate that diabetes alters cardiac endothelium angiogenic response, with differential effects of acute and chronic exposure to high-glucose conditions, consistent with the concept that endothelial cells may have a long-term "hyperglycemic memory" of the physiological environment in the body. Furthermore, endothelial cell exposure to strain significantly diminishes their angiogenic potential following strain application. Both diabetes and strain-associated deficiencies can be augmented in the proangiogenic nanofiber microenvironment. These findings may contribute to the development of novel approaches to reverse hyperglycemic memory of endothelium and enhance vascularization of the diabetic heart, where improved angiogenic and biomechanical responses can be the key factor to successful therapy.
authors.affiliation: Department of Biomedical, Chemical, and Environmental Engineering, University of Cincinnati, Cincinnati, Ohio;
authors.forename: Abdul Q
authors.initials: AQ
authors.lastname: Sheikh
authors.forename: Courtney
authors.initials: C
authors.lastname: Kuesel
authors.forename: Toloo
authors.initials: T
authors.lastname: Taghian
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Hurley
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hinton
authors.forename: Daria A
authors.initials: DA
authors.lastname: Narmoneva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001696:Biomechanical Phenomena; D049109:Cell Proliferation; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000502:physiology*; D003470:Culture Media; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D003470:Culture Media; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide
keywords: angiogenesis; biomechanical response; cardiomyopathy; diabetes; endothelial cell; nanofibers