This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Subproject Description Following traumatic spinal cord injury (SCI), significant vascular disruption occurs at the site(s) of injury. This interruption of vascular support to spinal tissue has been proposed to be a key mediator of multiple secondary injury cascades, all of which contribute to tissue damage and subsequent loss of function. While the precise molecular effector(s) governing this vascular dysfunction are not well understood, a small group of candidate molecules has been identified and include transforming growth factor-?1 (TGF-?1), vascular endothelial cell growth factor (VEGF), and matrix metalloproteases (MMPs). Importantly, the bioactivity of all these established effectors is modulated by plasminogen activator class of serine proteases although little data exist regarding their expression following SCI. Preliminary data have identified endothelial (EC) over-expression of plasminogen activator system (PAS) components uPA and its endogenous inhibitor PAI-1 as early regulators of neurovascular unit (NVU) pathology and may regulate functional recovery after SCI. In the current proposal, we will utilize these novel approaches, combined with in vivo treatment with small molecule inhibitors of PAS components, to address the following hypotheses: 1) Microvascular expression of PAS components negatively impacts EC survival, microvascular function, and white matter sparing/function following contusive thoracic SCI. 2) PAS induction in the EC compartment is the consequence of tissue ischemia initiated by traumatic SCI, which is responsible for evolving penumbral microvascular dysfunction, giving rise to inflammation and tissue loss. 3) Antagonism of PAS proteolytic induction following traumatic gray matter injury will result in enhanced EC survival, improved microvascular function, and decreased loss of neuropil due to secondary injury, an effect which is in part due to decreased activation of MMP-9. Results from these studies will provide critical insight into the pathologic transformation of the NVU resulting in decreased microvascular function following SCI, which is an invaluable initial step for designing effective vasoactive therapies for the treatment of SCI.
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