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Neurovascular injuries are leading causes of disability implicated in neurological dysfunction. Much of the Central Nervous System (CNS) homeostasis depends on concerted signaling between neurons, glial cells, and vasculature–the neurovascular unit (NVU). Neurovascular injuries disrupt the NVU causing hypoxia, ischemia, neuroinflammation, and neuronal death. Much of the neuroinflammatory responses associated with neurovascular injuries have been characterized, but the contribution of specific signaling pathways from the injured endothelium to inflammatory response remains to be established. To understand vascular-glial communication in the context of vascular injury, the Troy lab has used a mouse model of retinal vascular injury, retinal vein occlusion (RVO). The retina is a CNS enclosed tissue that allows live visualization of vascular and neuronal condition upon injury, genotype, and/or treatment. Previous studies in the laboratory determined that non-apoptotic expression of endothelial caspase-9 (EC Casp9) was key for the development of retinal edema, capillary ischemia, and neuronal death. Caspases are known for their role in mediating cell death, but how and if glial cells orchestrated outcomes remain unknown. This thesis work aimed to investigate the role of caspase-9 signaling in vascular-glial communication and its contribution to pro-inflammatory cytokine levels and neurodegeneration in neurovascular injury. To answer this, we first optimized the mouse model of RVO and profiled the levels of caspases in RVO retinas treated or untreated with a caspase-9 inhibitor using immunohistochemistry. Then, we used tamoxifen inducible endothelial and astroglial caspase-9 KO lines, subjected them to RVO and measured glial changes, cytokine levels, capillary ischemia, retinal edema, neuronal death, and vision dysfunction. We first found that RVO induces a range of cell-specific levels of caspases and that inhibition of caspase-9 specifically modulated the levels of endothelial caspase-9 and 8, neuronal caspase-9, 7, and 6, astroglial caspase-6, and leukocytic caspase-9 and 7. Our studies also suggest that endothelial caspase-9 induces a decrease in reactive microglia, inflammatory cytokines, cleaved- caspase-6 and GFAP cleavage in astrocytes. EC Casp9 deletion also altered changes in GFAP, nestin and AQP4 levels in Müller glia. Through investigating an astroglial caspase-9 KO, we discovered that astroglial caspase-9 could be upstream of astroglia caspase-6. Additionally, we found that astroglial caspase-9 loss protected hypoxic retinas from capillary ischemia but not from retinal edema nor neuronal death. Lastly, we used an optokinetic test to study the potential role of endothelial and astroglial caspase-9 in RVO-induced vision disfunction. Our results indicate that removing caspase-9 from endothelial cells or astrocytes protected contrast sensitivity damage in visual function one day post-RVO. In sum, the present thesis work demonstrates that endothelial and astroglial caspase-9 signaling can lead to inflammation and worsening of visual function in neurovascular injury.