Increasing Ang1/Tie2 expression by simvastatin treatment induces vascular stabilization and neuroblast migration after stroke.
In this study, we tested the hypothesis that the Angiopoietin 1 (Ang1)/Tie2 pathway mediates simvastatin-induced vascular integrity and migration of neuroblasts after stroke. Rats were subjected to 2 hrs of middle cerebral artery occlusion (MCAo) and treated, starting 1 day after stroke with or without simvastatin (1 mg/kg, daily) for 7 days. Simvastatin treatment significantly decreased blood-brain barrier (BBB) leakage and concomitantly, increased Ang1, Tie2 and Occludin expression in the ischaemic border (IBZ) compared to the MCAo control group. Simvastatin also significantly increased doublecortin (DCX, a marker of migrating neuroblasts) expression in the IBZ compared to control MCAo rats. DCX was highly expressed around vessels. To further investigate the signalling pathway of simvastatin-induced vascular stabilization and angiogenesis, rat brain microvascular endothelial cell (RBMEC) culture was employed. The data show that simvastatin treatment of RBMEC increased Ang1 and Tie2 gene and protein expression and promoted phosphorylated-Tie2 activity. Simvastatin significantly increased endothelial capillary tube formation, an index of angiogenesis, compared to non-treated control. Inhibition of Ang1 or knockdown of Tie2 gene expression in endothelial cells significantly attenuated simvastatin-induced capillary tube formation. In addition, simvastatin significantly increased subventricular zone (SVZ) explant cell migration compared to non-treatment control. Inhibition of Ang1 significantly attenuated simvastatin-induced SVZ cell migration. Simvastatin treatment of stroke increases Ang1/Tie2 expression and thereby reduces BBB leakage and promotes vascular stabilization. Ang1/Tie2 expression induced by simvastatin treatment promotes neuroblast micro-vascular coupling after stroke.
Chen
Jieli
J
Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA. jieli@neuro.hfh.edu
Cui
Xu
X
Zacharek
Alex
A
Chopp
Michael
M
D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009479:Neuropeptides / Q000378:metabolism; D062793:Occludin; D051381:Rats; D017208:Rats, Wistar; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
D042683:Angiopoietin-1; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D062793:Occludin; C568987:Ocln protein, rat; D019821:Simvastatin; D042787:Receptor, TIE-2