Candesartan stimulates reparative angiogenesis in ischemic retinopathy model

role of hemeoxygenase-1 (HO-1)

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)137-150
Number of pages14
JournalAngiogenesis
Volume18
Issue number2
DOIs
StatePublished - Jan 1 2015

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Heme Oxygenase-1
Vascular Endothelial Growth Factor A
Chemical activation
Blood Vessels
Endothelial cells
Neuroglia
Endothelial Cells
Cell Count
Pathologic Neovascularization
Ependymoglial Cells
candesartan
Peroxynitrous Acid
Angiogenesis Inducing Agents
Angiotensin Receptor Antagonists
Nitric Oxide Synthase Type II
Small Interfering RNA
Restoration
Retina
Perfusion
Stroke

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

Cite this

Shanab, A. Y., Elshaer, S., El-Azab, M. F., Soliman, S., Sabbineni, H., Matragoon, S., ... El-Remessy, A. B. (2015). Candesartan stimulates reparative angiogenesis in ischemic retinopathy model: role of hemeoxygenase-1 (HO-1). Angiogenesis, 18(2), 137-150. https://doi.org/10.1007/s10456-014-9451-4

Candesartan stimulates reparative angiogenesis in ischemic retinopathy model : role of hemeoxygenase-1 (HO-1). / Shanab, Ahmed Y.; Elshaer, Sally; El-Azab, Mona F.; Soliman, Sahar; Sabbineni, Harika; Matragoon, Suraporn; Fagan, Susan C.; El-Remessy, Azza B.

In: Angiogenesis, Vol. 18, No. 2, 01.01.2015, p. 137-150.

Research output: Contribution to journalArticle

Shanab, AY, Elshaer, S, El-Azab, MF, Soliman, S, Sabbineni, H, Matragoon, S, Fagan, SC & El-Remessy, AB 2015, 'Candesartan stimulates reparative angiogenesis in ischemic retinopathy model: role of hemeoxygenase-1 (HO-1)', Angiogenesis, vol. 18, no. 2, pp. 137-150. https://doi.org/10.1007/s10456-014-9451-4
Shanab, Ahmed Y. ; Elshaer, Sally ; El-Azab, Mona F. ; Soliman, Sahar ; Sabbineni, Harika ; Matragoon, Suraporn ; Fagan, Susan C. ; El-Remessy, Azza B. / Candesartan stimulates reparative angiogenesis in ischemic retinopathy model : role of hemeoxygenase-1 (HO-1). In: Angiogenesis. 2015 ; Vol. 18, No. 2. pp. 137-150.
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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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AB - 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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