DESCRIPTION (provided by applicant): Collateral status is an independent predictor of stroke outcome, as well as response to thrombolytic therapies in patients with ischemic stroke. Genetic factors contribute to the extent and development of native collaterals, whereas patients with metabolic syndromes are associated with poor collateral status during acute ischemic stroke. Diabetes increases the risk of stroke and exacerbates ischemic brain damage, although the impact of diabetes on collateral dynamics remains to be established. Our preliminary data suggest that using Doppler optical coherent tomography, a robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice and it continued to grow over the course of one week. However, an impairment of collateral recruitment was evident in the type-II-diabetic db/db mice immediately after MCAO. In the current application, we seek to investigate mechanisms underlying leptomeningeal collateral impairment. Aim1 will first determine the dynamics of retrograde flow compensation from ACA to MCA in the leptomeningeal collateral circulation after MCA stroke and their contribution to stroke outcome in mouse strains that can be used as surrogates for genetic variant of collateral circulation or for modeling pathophysiology in metabolic diseases. Aim 2 will decipher whether acute hyperglycemia contributes to the impairment of leptomeningeal collateral flow in the type II diabetic mice and whether short-term insulin therapy restores the collateral status after stroke. Aim 3 will determine the macrophage phenotype favorable for collaterogenesis/arteriogenesis via flow cytometry. We will also ascertain the role of CD36, a marker for M2 macrophage, in regulating collateral flow. Complementary approaches will determine whether by enhancing CD36 expression by pharmacological agent promote collateral flow in the diabetic mice or whether by adoptive transfer of control bone marrow cells into diabetic mice rescues the collateral status in the latter. This proof-of-concept study will provide a foundation for the development of therapeutic interventions to augment collateral flow for the treatment of ischemic stroke.

PUBLIC HEALTH RELEVANCE During stroke, some parts of the brain tissue are sustained by collateral flow through collateral vessels linking different vascular networks into one connecting transport system. The connecting collateral structure is determined by genetic factors, but the functional flow through the connecting structure can be disabled by metabolic disease such as diabetes. Per CDC, Veterans are reported to suffer from chronic conditions including diabetes, hypertension and stroke. Type II diabetes mellitus in particular, has also been identified to be one of the "presumptive diseases" associated with exposure to Agent Orange or other herbicides during military service. The current study will seek to understand how collateral flow affects the outcome of stroke and the underlying mechanisms regulating collateral circulation and collateral flow during ischemic stroke. Additional investigation will focus on the mechanisms by which diabetes impairs collateral status after stroke as a starting point to future development of therapies to improve collateral flow as a treatment for ischemic stroke.