title: Blocked angiogenesis in Galectin-3 null mice does not alter cellular and behavioral recovery after middle cerebral artery occlusion stroke.
abstract: Angiogenesis is thought to decrease stroke size and improve behavioral outcomes and therefore several clinical trials are seeking to augment it. Galectin-3 (Gal-3) expression increases after middle cerebral artery occlusion (MCAO) and has been proposed to limit damage 3days after stroke. We carried out mild MCAO that damages the striatum but spares the cerebral cortex and SVZ. Gal-3 gene deletion prevented vascular endothelial growth factor (VEGF) upregulation after MCAO. This inhibited post-MCAO increases in endothelial proliferation and angiogenesis in the striatum allowing us to uniquely address the function of angiogenesis in this model of stroke. Apoptosis and infarct size were unchanged in Gal-3(-/-) mice 7 and 14 days after MCAO, suggesting that angiogenesis does not affect lesion size. Microglial and astrocyte activation/proliferation after MCAO was similar in wild type and Gal-3(-/-) mice. In addition, openfield activity, motor hemiparesis, proprioception, reflex, tremors and grooming behaviors were essentially identical between WT and Gal-3(-/-) mice at 1, 3, 7, 10 and 14 days after MCAO, suggesting that penumbral angiogenesis has limited impact on behavioral recovery. In addition to angiogenesis, increased adult subventricular zone (SVZ) neurogenesis is thought to provide neuroprotection after stroke in animal models. SVZ neurogenesis and migration to lesion were overall unaffected by the loss of Gal-3, suggesting no compensation for the lack of angiogenesis in Gal-3(-/-) mice. Because angiogenesis and neurogenesis are usually coordinately regulated, identifying their individual effects on stroke has hitherto been difficult. These results show that Gal-3 is necessary for angiogenesis in stroke in a VEGF-dependant manner, but suggest that angiogenesis may be dispensable for post-stroke endogenous repair, therefore drawing into question the clinical utility of augmenting angiogenesis.
authors.affiliation: University of Oxford, Department of Physiology, Anatomy and Genetics, University of Oxford, OX1 3QX, UK.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Young
authors.affiliation: University of Oxford, Department of Physiology, Anatomy and Genetics, University of Oxford, OX1 3QX, UK.
authors.forename: Osama
authors.initials: O
authors.lastname: Al-Dalahmah
authors.affiliation: University of Oxford, Department of Physiology, Anatomy and Genetics, University of Oxford, OX1 3QX, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Lewis
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, OX1 3QX, UK.
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Brooks
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, OX1 3QX, UK.
authors.forename: Micaela M
authors.initials: MM
authors.lastname: Jenkins
authors.affiliation: Institut Jacques Monod, UMR CNRS 7592, Université Paris Diderot, 75205 Paris 13, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Poirier
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, OX1 3QX, UK.
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Buchan
authors.affiliation: University of Oxford, Department of Physiology, Anatomy and Genetics, University of Oxford, OX1 3QX, UK. Electronic address: francis.szele@dpag.ox.ac.uk.
authors.forename: Francis G
authors.initials: FG
authors.lastname: Szele
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D002552:Cerebral Ventricles / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000235:genetics; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D037502:Galectin 3 / Q000172:deficiency* / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D005911:Gliosis / Q000209:etiology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D008297:Male; D001523:Mental Disorders / Q000209:etiology* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D055495:Neurogenesis / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D037502:Galectin 3; C485095:Lgals3 protein, mouse; D042461:Vascular Endothelial Growth Factor A
keywords: 5-bromo-2-deoxyuridine; ANOVA; Angiogenesis; BrdU; CBF; CSF; Dcx; ECM; GFAP; Gal-3; Galectin-3; H/I; Ischemia; MCA; MCAO; Middle cerebral artery occlusion; Migration; NeuN; Neural repair; Neurogenesis; OB; PCP; PECAM-1; PHi3; RMS; SVZ; Subependymal zone; TUNEL; VEGF; WT; ace tub; acetylated tubulin; analysis of variance; cerebral blood flow; cerebrospinal fluid; doublecortin; extracellular matrix; gamma-tubulin; glial fibrillary acidic protein; hypoxia ischemia; middle cerebral artery; middle cerebral artery occlusion; neuronal nuclei; olfactory bulb; phosphorylated histone H3; planar cell polarity; platelet endothelial cell adhesion molecule-1; rostral migratory stream; subventricular zone; terminal deoxynucleotidyl transferase dUTP nick end labeling; vascular endothelial growth factor; wild type; β-cat; β-catenin; γ-tub