PROJECT SUMMARY Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, accounts for up to 15% of all strokes. ICH, which affects 67,000 Americans annually, induces the highest acute mortality and the worst long- term neurological outcomes of all types of stroke. Primary ICH is caused by the rupture of small vessels damaged by chronic hypertension or cerebral amyloid angiopathy. The resultant hematoma disrupts neural networks and damages the vascular architecture, culminating in a loss of brain function and the need for lifelong medical assistance. Re-establishment of a functional cerebrovascular network of small arteries and arterioles is a prerequisite for the removal of damaged tissue and for restoration of cerebral blood flow to deliver nutrients, trophic factors, and stem cells within the injured brain. Thus, there is a dire need for neurorestorative therapies that provide cerebrovascular recovery after ICH. Remote ischemic conditioning (RIC), the repetitive delivery of sub-lethal ischemia to a remote limb, demonstrated safety, versatility, and efficacy in early stage clinical trials; however, the utility of RIC after ICH remains understudied. The objective of this proposal is to test the overarching hypothesis that RIC induces vascular remodeling and improves long-term neurological function via anti-inflammatory myeloid cell activation after ICH. Specific Aim 1 will test the hypothesis that myeloid AMPK?1 mediates RIC-induced vascular repair after ICH. Specific Aim 2 will test the hypothesis that RIC increases angiogenesis via Del-1 release after ICH. Specific Aim 3 will test the hypothesis that delayed implementation of RIC improves chronic ICH outcomes in a sex- and age-independent manner. Expected outcomes of the proposed research include the identification of RIC as a clinically-safe, non-invasive intervention to promote cerebrovascular recovery after ICH. As ICH patients exhibit high permanent disability rates that diminish quality of life, our proposed research will identify a simple therapy to harness an endogenous pathway of neurological repair, providing an innovative and cost-effective approach to rehabilitate chronic ICH patients. .
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