Diabetic retinopathy (DR) is a primary cause of blindness of working age adults in the Western world. Early pericyte dropout and endothelial cell death result in the formation of acellular capillaries, which cause retinal hypoxia and ischemia and are important contributors to DR development. We have shown have that hematopoietic stem and endothelial precursor cells (EPC) readily home to the retina in healthy animals, but that EPC of diabetic animal and humans have a migratory defect. Our preliminary studies demonstrate that EPC dysfunction may provide a novel mechanism for development of acellular capillaries in diabetic retinopathy. Our data suggest that within EPCs, nitric oxide (NO) plays a key role in regulating the actin polymerization mediator, vasodilator-stimulated phosphoprotein (VASP). In diabetes, reduced bioavailability of NO can occur as a result of alterations in growth factor/cytokine receptor balance, downstream signaling, or downregulation of NO synthase (NOS) activation. Reduced NO can alter actin polymerization affecting EPC migration and their ability to carry out endothelial repair. Our hypothesis is that in diabetic individuals reduced NO bioavailability results in decreased EPC migration, attachment and invasion contributing to inadequate endothelial repair and development of acellular capillaries. State-of-the- art imaging, fluorescent activated cell sorter analysis, novel in vitro culture assays and diabetic animal models will be used in combination with biochemical and molecular biological techniques to test our hypothesis. We propose the following specific aims:
Specific Aim 1 : Our hypothesis predicts that diabetic EPCs will be unable to home to the retina and repopulate acellular capillaries whereas EPCs from normals will. Diabetic mice that have developed acellular retinal capillaries will be injected systemically with EPCs from nondiabetic rodents and the degree of vascular repair examined.
Specific Aim 2 : Our hypothesis predicts that NO regulates EPC migration .directly by promoting cytoskeletal changes. We will determine which factors regulate EPC NOS isoform expression and NO generation and delineate the NO signaling pathway that regulates cytoskeletal dysfunction in diabetic EPCs.
Specific Aim 3 : Our hypothesis predicts that diabetic CD34+ EPC cells have defective attachment and invasion. We will determine whether EPC attachment is dependent upon inherent properties of the EPC or the local matrix environment and evaluate human diabetic and nondiabetic CD34+ cell attachment to normal and glycated matrix. The exciting implication of our hypothesis is that early repair of the EPC migratory defect may deter the subsequent development of proliferative diabetic retinopathy.
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