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Candesartan stimulates reparative angiogenesis in ischemic retinopathy model: role of hemeoxygenase-1 (HO-1)

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Abstract

Ischemic diseases such as stroke and proliferative retinopathy are characterized by hypoxia-driven release of angiogenic factors such as vascular endothelial growth factor (VEGF). However, revascularization of the ischemic areas is inadequate, resulting in impaired neuro-vascular function. We aim to examine the vascular protective effects of candesartan, an angiotensin receptor blocker, in an ischemic retinopathy mouse model. Vascular density, number of tip cells, and perfusions of capillaries were assessed. Activation of Muller glial cells and levels of peroxynitrite, VEGF, VEGFR2, inducible nitric oxide synthase, hemeoxygenase-1 (HO-1) were assessed. Proangiogenic effects of candesartan were examined in human endothelial cells (EC) that were cultured in normoxia or hypoxia and transduced with siRNA against HO-1. Candesartan (1 mg/kg) and (10 mg/kg) decreased hypoxia-induced neovascularization by 67 and 70 %, respectively. Candesartan (10 mg/kg) significantly stimulated the number of tip cells and physiological revascularization of the central retina (45 %) compared with untreated pups. The effects of candesartan coincided with reduction of hypoxia-induced Muller glial activation, iNOS expression and restoration of HO-1 expression with no significant change in VEGF levels. In vitro, silencing HO-1 expression blunted the ability of candesartan to induce VEGF expression under normoxia and VEGFR2 activation and angiogenic response under both normoxia and hypoxia. These findings suggest that candesartan improved reparative angiogenesis and hence prevented pathological angiogenesis by modulating HO-1 and iNOS levels in ischemic retinopathy. HO-1 is required for VEGFR2 activation and proangiogenic action of candesartan in EC. Candesartan, an FDA-approved drug, could be repurposed as a potential therapeutic agent for the treatment of ischemic diseases.

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Abbreviations

VEGF:

Vascular endothelial growth factor

p:

Postnatal day

Cand:

Candesartan

ROP:

Retinopathy of prematurity

DR:

Diabetic retinopathy

iNOS:

Inducible nitric oxide synthase

HO-1:

Hemeoxygenase-1

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Acknowledgments

The authors would like to thank Astra-Zeneca for providing candesartan. Authors are indebted to Megan L. Bartasis for providing help with Western blot. This work was supported by grants from EY-022408, JDRF (2-2008-149) and Culver Vision Discovery Institute to ABE, postdoctoral Fellowship from Islamic Development Bank to M.F.E., predoctoral fellowship (12PRE12030197) from American Heart Association for S.S., VA Merit award (BX000891) to S.C.F.

Conflict of interest

The authors have nothing to disclose. The contents do not represent the views of the Department of Veterans Affairs or the United States government.

Author information

Author notes

  1. Mona F. El-Azab

    Present address: Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt

  2. Sahar Soliman

    Present address: Yale University, New Haven, CT, USA

Authors and Affiliations

  1. Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, 30912, USA

    Ahmed Y. Shanab, Sally L. Elshaer, Mona F. El-Azab, Sahar Soliman, Harika Sabbineni, Suraporn Matragoon, Susan C. Fagan & Azza B. El-Remessy

  2. Culver Vision Discovery Institute, Georgia Regents University, Augusta, GA, USA

    Ahmed Y. Shanab, Sally L. Elshaer, Mona F. El-Azab, Sahar Soliman, Harika Sabbineni, Suraporn Matragoon & Azza B. El-Remessy

  3. Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA

    Ahmed Y. Shanab, Sally L. Elshaer, Mona F. El-Azab, Sahar Soliman, Harika Sabbineni, Suraporn Matragoon, Susan C. Fagan & Azza B. El-Remessy

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Correspondence to Azza B. El-Remessy.

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Shanab, A.Y., Elshaer, S.L., El-Azab, M.F. et al. Candesartan stimulates reparative angiogenesis in ischemic retinopathy model: role of hemeoxygenase-1 (HO-1). Angiogenesis 18, 137–150 (2015). https://doi.org/10.1007/s10456-014-9451-4

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