The Role of contralateral cerebrovascular myogenic dysfunction in stroke

Abstract

Acute ischemic stroke (AIS) is the fourth leading cause of death and disability in the United States. The only successful therapeutic target identified for the 800,000 annual victims of AIS is the cerebral vasculature. This emphasizes the importance of maintaining a well-functioning vasculature with a well-optimized myogenic tone to supply the necessary nutrients, and even the requisite concentration of neuroprotectant to the jeopardized tissue, but at the same time avoiding hemorrhage. While early studies described that ischemia/reperfusion (I/R) reduces cerebral perfusion in the nonischemic hem1sphere as well, the underlying mechanisms and the impact of this contralateral vascular dysfunction on stroke outcomes have long been neglected. The goal of this proposal is to begin addressing this problem by focusing on the myogenic reactivity in ischemic and contralateral nonischemic hemispheres in experimental models with different stroke severity. Our global hypothesis is that contralateral myogenic dysfunction following 1/R contributes significantly to stroke outcomes. This hypothesis will be tested by I) determining the impact of 1/R on myogenic reactivity in ischemic and contralateral hemispheres, and 2) determining the impact of contralateral myogenic dysfunction in conditions associated with poor stroke outcomes. This study will reveal the critical role of vascular d~function in nonischemic hemisphere in worsening stroke outcomes as well as the underlying mechanisms. The rationale is that once the mechanisms and modulators of cerebrovascular function and perfusion in both hemispheres are known, it will be possible to develop more effective strategies to deliver neuroprotective therapies to improve stroke outcomes and recovery. Moreover, these experiments have the potential to challenge the concept that contralateral hemisphere can serve as a control in preclinical stroke studies.