Our recent findings of robust neurovascular protection with early blood pressure (BP) lowering after stroke has prompted us to, in this competitive renewal, continue to elucidate mechanisms of the protective effects of BP management in the hours after stroke. Our long term goal is to understand the pathways of neurovascular injury in the brain during and after ischemic stroke in order to design and implement better treatments for stroke patients. In the first funding period, we determined that BP lowering after reperfusion is neurovascularprotective, and the best outcomes are achieved when angiotensin blockade is employed. The central hypothesis for the proposed research is that vascular protection, accomplished by early BP lowering, activates endogenous survival proteins, including those of the antiapoptosis and angiogenic pathways, even without reperfusion. We plan to test our central hypotheses and accomplish the overall objectives of this application through the following specific aims:
Specific Aim #1 : Determine the extent to which recovery after cerebral ischemia and BP lowering is dependent upon the presence and method of reperfusion. Our working hypothesis is that the neurovascular protective effect of early BP lowering persists whether or not reperfusion is achieved, mechanically or by thrombolysis.
Specific Aim #2 : Determine the extent to which early BP lowering after cerebral ischemia induces endogenous survival pathways. Our working hypothesis is that early BP lowering induces a """"""""post conditioning""""""""- like state that results in persistent vascular protection, leading to recovery. This protection is reliant on antiapoptotic Akt and proangiogenic VEGF activation.

Public Health Relevance

Project Narrative: Relevance to Veterans Health: Central nervous system injury and related disorders is a stated area of priority in the VA health care mission. Stroke is a leading cause of death and disability in VA patients and is very costly to the VA system. Strategies to achieve effective treatment of stroke have the potential for a large impact on VA patients and their families. This project is both mechanistic and translational in that the results will be used to design a clinical trial in stroke patients.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cardiovascular Studies A (CARA)
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Charlie Norwood VA Medical Center
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Ahmed, Heba A; Ishrat, Tauheed; Pillai, Bindu et al. (2018) Role of angiotensin system modulation on progression of cognitive impairment and brain MRI changes in aged hypertensive animals - A randomized double- blind pre-clinical study. Behav Brain Res 346:29-40
Hafez, Sherif; Abdelsaid, Mohammed; Fagan, Susan C et al. (2018) Peroxynitrite-Induced Tyrosine Nitration Contributes to Matrix Metalloprotease-3 Activation: Relevance to Hyperglycemic Ischemic Brain Injury and Tissue Plasminogen Activator. Neurochem Res 43:259-266
Fouda, Abdelrahman Y; Alhusban, Ahmed; Ishrat, Tauheed et al. (2017) Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke. Mol Neurobiol 54:661-670
Alhusban, Ahmed; Kozak, Anna; Pillai, Bindu et al. (2017) Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension. PLoS One 12:e0178867
Fouda, Abdelrahman Y; Pillai, Bindu; Dhandapani, Krishnan M et al. (2017) Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol 799:128-134
Li, Weiguo; Ward, Rebecca; Valenzuela, John Paul et al. (2017) Diabetes Worsens Functional Outcomes in Young Female Rats: Comparison of Stroke Models, Tissue Plasminogen Activator Effects, and Sexes. Transl Stroke Res :
Hafez, Sherif; Abdelsaid, Mohammed; El-Shafey, Sally et al. (2016) Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke. Stroke 47:843-51
Coucha, Maha; Abdelsaid, Mohammed; Li, Weiguo et al. (2016) Nox4 contributes to the hypoxia-mediated regulation of actin cytoskeleton in cerebrovascular smooth muscle. Life Sci 163:46-54
Ergul, Adviye; Hafez, Sherif; Fouda, Abdelrahman et al. (2016) Impact of Comorbidities on Acute Injury and Recovery in Preclinical Stroke Research: Focus on Hypertension and Diabetes. Transl Stroke Res 7:248-60
Ergul, Adviye; Valenzuela, John Paul; Fouda, Abdelrahman Y et al. (2015) Cellular connections, microenvironment and brain angiogenesis in diabetes: Lost communication signals in the post-stroke period. Brain Res 1623:81-96

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