Extracellular microenvironment for the regulation of endothelial angiogenic responses

Diabetes mellitus is a growing epidemic in United States, affecting 8.3 % of the total population, including 25.8 million children and adults. Diabetes is associated with several major long-term complications, including diabetes-induced myocardial injury (diabetic cardiomyopathy, DCM) and diabetic ulcers. These complications are associated with vascular pathologies such as abnormal angiogenesis (formation of blood vessels) along with altered biomechanical and cellular microenvironment. Vascular tissue engineering approaches have been realized as a beneficial means of facilitating the treatments for these diabetic conditions. However, these vascular tissue engineering approaches have had limited success due to the lack of mechanistic understanding of diabetes-induced vascular pathologies, and the development of adequately vascularized tissue. Moreover, little is known about the effects of extracellular signals on angiogenic responses and underlying intracellular signaling cascades in diabetic conditions. This lack of mechanistic understanding impedes technological advancement of new strategies for vascular tissue engineering therapies for DCM and diabetic ulcers.;The long-term goal of this research is to understand diabetes-induced pathological alterations in endothelial angiogenic responses and to augment the angiogenic process and intracellular signaling by modulating the extracellular environment, such as stimulating angiogenesis via scaffold or external electric field. The central hypothesis of this research is that pro-angiogenic external environment can augment endothelial angiogenic responses and intracellular signaling under normal and diabetic conditions.;The results from this dissertation research help identify the effects of diabetes on the cardiac endothelial angiogenic responses at the molecular and cellular levels. The RAD16-II nanofiber system was utilized as a pro-angiogenic microenvironment to augment cardiac endothelial angiogenic and biomechanical responses in diabetic cardiomyopathy. The effects of an externally applied electric field on endothelial angiogenic responses and underlying signaling mechanisms were elucidated for the treatment of diabetic chronic wounds. The findings of this research contribute towards understanding the diabetes-induced vascular pathologies and augmenting altered vascular cell responses using vascular tissue engineering approaches.