Arteriogenesis refers to the growth of a functional collateral blood supply. In the brain, cerebrovascular collaterals form networks of anastomosing arterioles that are clinically documented to perfuse stroke-affected tissue during cerebral ischemia and attenuate brain injury. While strategies that target arteriogenesis against acute ischemic stroke (AIS) are of significant therapeutic interest, mechanisms and a means to improve cerebrovascular collateral circulation during AIS remain unknown. The current proposal rests on a key in vivo observation that prophylactic supplementation of lesser-characterized natural vitamin E tocotrienol (TCT), improves cerebrovascular collateral circulation and attenuates AIS-induced brain injury. Prophylactic TCT supplementation therefore serves as a powerful tool to study cerebrovascular collateral biology during AIS. The overall objective of the proposal is to characterize the effects of prophylactic TCT on cerebrovascular collateral perfusion during stroke and to identify a mechanistic basis for TCT improvement of cerebrovascular collateral circulation. FITC-lectin tagging of cerebrovascular collaterals is proposed for laser capture microdissection experiments and downstream molecular analyses. This approach will enable for the first time the specific collection of perfused cerebrovascular collaterals as well as non-patent vessels from stroke-affected tissue for mechanistic study. The functional significance of a TCT-induced anti-proteolytic shift in cerebrovascular collaterals is investigated. TCT induction of tissue inhibitor of metalloproteinase 1 (TIMP1) and miR-29b are investigated as molecular targets of interest for mature collateral anastomoses in the brain. As TCT is a safe, natural nutrient, proposal outcomes may quickly translate toward clinical applications for high-risk stroke patients, such as those who suffered a prior stroke or a transient ischemic attack (TIA).
Aim 1. Characterize the effects of TCT on cerebrovascular collateral perfusion during acute ischemic stroke (AIS). Central Hypothesis: Prophylactic TCT supplementation improves cerebrovascular collateral blood flow at the stroke-affected site.
Aim 2. Determine the functional significance of TCT to affect TIMP1 expression in cerebrovascular collaterals. Central Hypothesis: TCT facilitates an optimal balance of TIMP1 expression that favors functional cerebrovascular collateral formation.
Aim 3. Examine the significance of TCT-sensitive miR-29b in cerebrovascular collaterals. Central Hypothesis: Elevated miR-29b in response to TCT silences MMP-2 in cerebrovascular collaterals during stroke.
This proposal investigates the unique ability of natural vitamin E tocotrienol (TCT) to improve alternative conduits of blood flow, called collaterals, to stroke-affected brain tissue. Using a novel laser dissection approach, mechanisms of improved collateral blood flow are studied. As TCT is a safe, natural nutrient, proposal outcomes may quickly translate toward clinical therapies for more than 7 million Americans at high- risk for ischemic stroke.
Showing the most recent 10 out of 58 publications
