Project 463116

Ischemic stroke, caused by blood vessel occlusion, is the third leading cause of death in Canada and a leading cause of disability. Rapid reestablishment of vascular function is critical, as the restriction in oxygen is responsible for neuronal loss. While a partial functional recovery typically occurs due to the neovascular plasticity of the brain, debilitating damage usually remains and has a devastating impact on quality of life. Although increasing blood vessel growth after stroke has therapeutic potential, efforts have not been successful in regrowing functional blood vessels in the ischemic area. Indeed, current treatments promoting blood vessel growth increase blood vessel permeability and, consequently, edema, inflammation, and the risk of hemorrhages. Thus, it is crucial to identify new treatments that regulate both new blood vessel growth and permeability. In the healthy brain, new blood vessels simultaneously grow and form a unique and selective blood-brain barrier to protect neuron homeostasis. We have recently uncovered a new paradigm in which a protein called transforming growth factor B (TGFB) can regulate new blood vessel growth and leakiness. While the mechanisms remain unknown, we have recently discovered that the effects of TGFB in blood vessels can be mediated by a protein called SOX9, which is a regulator of gene expression. Therefore, we propose to elucidate how TGFB and SOX9 regulate the growth of blood vessels in the brain, and we hypothesize that these proteins could represent therapeutic opportunities to promote the regrowth of functional blood vessels and protect brain function after stroke. To achieve this, we will use several state-of-the-art techniques to assess gene expression in single cells, to visualize blood vessels in specific regions of the brain, and to study a mouse model of ischemic stroke. This study could lay the foundation for developing new therapeutic strategies for brain revascularization following ischemic stroke.