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Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia

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Abstract

The pro-survival effect of VEGF-B has been documented in different in vivo and in vitro models. We have previously shown an enhanced VEGF-B expression in response to candesartan treatment after focal cerebral ischemia. In this study, we aimed to silence VEGF-B expression to assess its contribution to candesartan’s benefit on stroke outcome. Silencing VEGF-B expression was achieved by bilateral intracerebroventricular injections of lentiviral particles containing short hairpin RNA (shRNA) against VEGF-B. Two weeks after lentiviral injections, rats were subjected to either 90 min or 3 h of middle cerebral artery occlusion (MCAO) and randomized to intravenous candesartan (1 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 or 72 h and brains were collected and analyzed for hemoglobin (Hb) excess and infarct size, respectively. Functional outcome at 24, 48 and 72 h was assessed blindly. Candesartan treatment improved neurobehavioral and motor function, and decreased infarct size and Hb. While silencing VEGF-B expression diminished candesartan’s neuroprotective effect, candesartan-mediated vascular protection was maintained even in the absence of VEGF-B suggesting that this growth factor is not the mediator of candesartan’s vascular protective effects. However, VEGF-B is a mediator of neuroprotection achieved by candesartan and represents a potential drug target to improve stroke outcome. Further studies are needed to elucidate the underlying molecular mechanisms of VEGF-B in neuroprotection and recovery after ischemic stroke.

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Abbreviations

ARBs:

Angiotensin II type-1 receptor blockers

KD:

VEGF-B knockdown

MCAO:

Middle cerebral artery occlusion

NTC:

Non-targeting control

shRNA:

Short hairpin RNA

VEGF-B:

Vascular endothelial growth factor-B

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Acknowledgements

This work was supported by the National Institute of Health [RO1-NS063965 (SCF), RO1-NS083559 (AE), R01NS097800-01 (TI)], Veterans Affairs Merit Review [BX-000891 (SCF), BX-BX000347 (AE)], and the American Heart Association (12PRE12030197 (SS)). Adviye Ergul is a Research Career Scientist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia. The authors gratefully acknowledge Abdelrahman Fouda for the technical assistance with animal tissue collection.

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Author notes

  1. Tauheed Ishrat and Sahar Soliman have contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), 855 Monroe Ave, Rm 231-Wittenborg bldg., Memphis, TN, 38163, USA

    Tauheed Ishrat

  2. Charlie Norwood VA Medical Center, and Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA

    Sahar Soliman, Wael Eldahshan, Bindu Pillai, Adviye Ergul & Susan C. Fagan

  3. Department of Physiology, Augusta University, Augusta, GA, USA

    Adviye Ergul

  4. Department of Neurology, Augusta University, Augusta, GA, USA

    Susan C. Fagan

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  1. Tauheed Ishrat
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  2. Sahar Soliman
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  3. Wael Eldahshan
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  4. Bindu Pillai
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Correspondence to Tauheed Ishrat.

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The contents do not represent the views of the Department of Veterans Affairs or the United States government.

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Ishrat, T., Soliman, S., Eldahshan, W. et al. Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia. Neurochem Res 43, 1869–1878 (2018). https://doi.org/10.1007/s11064-018-2604-x

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