title: Coexpression of angiopoietin-1 with VEGF increases the structural integrity of the blood-brain barrier and reduces atrophy volume.
abstract: Vascular endothelial growth factor (VEGF)-induced neovasculature is immature and leaky. We tested if coexpression of angiopoietin-1 (ANG1) with VEGF improves blood-brain barrier (BBB) integrity and VEGF neuroprotective and neurorestorative effects using a permanent distal middle cerebral artery occlusion (pMCAO) model. Adult CD-1 mice were injected with 2 × 10(9) virus genomes of adeno-associated viral vectors expressing VEGF (AAV-VEGF) or ANG1 (AAV-ANG1) individually or together in a 1:1 ratio into the ischemic penumbra 1 hour after pMCAO. AAV-LacZ was used as vector control. Samples were collected 3 weeks later. Compared with AAV-LacZ, coinjection of AAV-VEGF and AAV-ANG1 reduced atrophy volume (46%, P=0.004); injection of AAV-VEGF or AAV-ANG1 individually reduced atrophy volume slightly (36%, P=0.08 and 33%, P=0.09, respectively). Overexpression of VEGF reduced tight junction protein expression and increased Evans blue extravasation. Compared with VEGF expression alone, coexpression of ANG1 with VEGF resulted in upregulation of tight junction protein expression and reduction of Evans blue leakage (AAV-ANG1/AAV-VEGF: 1.4 ± 0.3 versus AAV-VEGF: 2.8 ± 0.7, P=0.001). Coinjection of AAV-VEGF and AAV-ANG1 induced a similar degree of angiogenesis as injection of AAV-VEGF alone (P=0.85). Thus, coexpression of ANG1 with VEGF improved BBB integrity and resulted in better neuroprotection compared with VEGF expression alone.
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, California 94110, USA.
authors.forename: Fanxia
authors.initials: F
authors.lastname: Shen
authors.forename: Espen J
authors.initials: EJ
authors.lastname: Walker
authors.forename: Lidan
authors.initials: L
authors.lastname: Jiang
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.forename: Baoliang
authors.initials: B
authors.lastname: Sun
authors.forename: Fransisca
authors.initials: F
authors.lastname: Heriyanto
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.forename: Hua
authors.initials: H
authors.lastname: Su
mesh_terms: D042683:Angiopoietin-1 / Q000096:biosynthesis*; D000818:Animals; D001284:Atrophy; D001812:Blood-Brain Barrier / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D000229:Dependovirus / Q000235:genetics; D005822:Genetic Vectors; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007763:Lac Operon / Q000235:genetics; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics; D010539:Permeability; D010957:Plasmids; D019108:Tight Junctions / Q000378:metabolism; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D042683:Angiopoietin-1; D042461:Vascular Endothelial Growth Factor A