DYSTROPHIN DEFICIENCY AND ENDOTHELIAL CELL FUNCTION IN THE ANGIOGENIC RESPONSE TO EXERCISE AND ISCHEMIA

Duchenne muscular dystrophy (DMD) is a severe genetic disease which results in progressive muscle degeneration. Although the deficient gene product has been identified as dystrophin, the relationship between the protein’s absence and muscle pathology is not understood. Recent studies have suggested that Nitric Oxide (NO) plays a key role in the pathogenesis of DMD. NO is a vasorelaxant produced by skeletal muscle during physical exercise and by endothelial cells in response to an increase of flow. In DMD patients and in the mouse model of dystrophy (mdx), NO production is impaired. These findings strongly suggest that a novel vascular mechanism contributes to the pathogenesis of DMD: the decrease of blood flow and oxygen delivery in exercising skeletal muscle results in functional ischemia which accelerates progressive muscle degeneration. It is therefore important to study the role of dystrophin in vascular cell functions in order to better understand the involvement of the vascular system in DMD pathology. The goals of the research project are: 1) Analyze the flow-mediated molecular responses in dystrophin deficient endothelial cells 2) Establish the effects of dystrophin deficiency on endothelial cell function during blood vessels formation that occurs in ischemia and physical exercise 3) Establish a stem cell therapy approach to correct vascular abnormalities in DMD This project will provide information on the vascular involvement in DMD and will help develop stem cell therapy, strategies to attenuate skeletal muscle degeneration.