title: Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: role of vascular endothelial growth factors A and B.
abstract: Angiogenesis is a key component of recovery after stroke. Angiotensin II receptor blocker (ARB) treatment improves neurobehavioral outcome and is associated with enhanced angiogenesis after stroke. The purpose of this study is to investigate the temporal pattern of the ARB proangiogenic effect in the ischemic brain and its association with vascular endothelial growth factors VEGF-A and VEGF-B. Wistar rats were exposed to 90-minute middle cerebral artery occlusion and treated with candesartan (1 mg/kg) at reperfusion. The proangiogenic potential of the cerebrospinal fluid was determined at 8, 24, 48, and 72 hours using an in vitro Matrigel tube formation assay. In addition, the expression of VEGF-A and VEGF-B was measured in brain homogenates using Western blotting at the same time points. A single candesartan dose induced a prolonged proangiogenic effect and a prolonged upregulation of VEGF-A and VEGF-B in vivo. In the ischemic hemisphere, candesartan treatment was associated with stabilization of hypoxia-inducible factor-1α and preservation of angiopoietin-1. The effect of ARB treatment on endothelial cells was studied in vitro. Our results identified brain endothelial cells as one target for the action of ARBs and a source of the upregulated VEGF-A and VEGF-B, which exerted an autocrine angiogenic response, in addition to a paracrine neuroprotective effect. Taken together, this study highlights the potential usefulness of augmenting the endogenous restorative capacity of the brain through the administration of ARBs.
authors.affiliation: Program in Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia (S.S., T.I., P.R.S., A.E., A.B.E., S.C.F.); Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia (S.S., T.I., P.R.S., A.E., A.B.E., S.C.F.); and Departments of Psychiatry (A.P.), Medicine (P.R.S.), Physiology (A.E.), Pharmacology and Toxicology (A.B.E.), and Neurology (S.C.F.), Georgia Regents University, Augusta, Georgia.
authors.forename: Sahar
authors.initials: S
authors.lastname: Soliman
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Anilkumar
authors.initials: A
authors.lastname: Pillai
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D018929:Cell Culture Techniques; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D042561:Vascular Endothelial Growth Factor B / Q000096:biosynthesis*
chemical_list: D042683:Angiopoietin-1; C467629:Angpt1 protein, rat; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D013777:Tetrazoles; C581256:VEGFB protein, rat; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; C467498:vascular endothelial growth factor A, rat; D005947:Glucose; D010100:Oxygen; C081643:candesartan