Angiopoietin/Tie2 pathway mediates type 2 diabetes induced vascular damage after cerebral stroke

• Main Authors: Xu Cui, Michael Chopp, Alex Zacharek, Xinchun Ye, Cynthia Roberts, Jieli Chen
• Format: Article
• Language: English
• Published: Elsevier 2011-07-01
• Series: Neurobiology of Disease
• Subjects: Diabetes; Vascular damage; Angiopoietin; Stroke; Mice
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996111001227

We investigated the changes and the molecular mechanisms of cerebral vascular damage after stroke in type-2 diabetic (T2DM) mice. Adult male db/db T2DM and wild-type (WT) mice were subjected to transient middle cerebral artery occlusion (MCAo) and sacrificed 24 hours after MCAo. T2DM-mice exhibited significantly increased blood glucose, brain hemorrhagic rate, mortality and cerebrovascular density, but decreased cerebrovascular diameter, arteriolar density and arterial mural cell numbers in the ischemic brain compared with WT mice. The hemorrhagic rate was significantly correlated with the mortality (r=0.85). T2DM-mice also exhibited increased blood–brain barrier leakage and concomitantly, increased Angiopoietin2, but decreased Angiopoietin1, Tie2 and tight junction protein expression in the ischemic brain. Angiopoietin1 gene expression also significantly decreased in the common carotid artery (CCA) in T2DM-mice compared with WT mice after stroke. To further test the effects of T2DM on cerebrovascular damage, we performed in vitro studies. The capillary-like tube formation of primary cultured mouse brain endothelial cells (MBECs) significantly increased, but artery cell migration in the primary CCA cultures significantly decreased both in Sham and MCAo T2DM-mice compared with the WT mice. Angiopoietin1 treatment significantly increased artery cell migration in T2DM-CCA after MCAo. Tie2-FC, a neutralized Tie2 antibody, significantly decreased artery cell migration in WT-CCA after MCAo. Therefore, decreased Angiopoietin1/Tie2 and increased Angiopoietin2 expression may contribute to diabetes-induced vascular damage after stroke.