Vascular protection in diabetic stroke: Role of matrix metalloprotease- dependent vascular remodeling

Mostafa M. Elgebaly, Roshini Prakash, Weiguo Li, Safia Ogbi, Maribeth H Johnson, Erin M. Mezzetti, Susan C. Fagan, Adviye Ergul

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Temporary focal ischemia causes greater hemorrhagic transformation (HT) in diabetic Goto-Kakizaki (GK) rats, a model with increased cerebrovascular matrix metalloprotease (MMP) activity and tortuosity. The objective of the current study was to test the hypotheses that (1) diabetes-induced cerebrovascular remodeling is MMP dependent and (2) prevention of vascular remodeling by glucose control or MMP inhibition reduces HT in diabetic stroke. Control and GK rats were treated with vehicle, metformin, or minocycline for 4 weeks, and indices of remodeling including vascular tortuosity index, lumen diameter, number of collaterals, and middle cerebral artery (MCA) MMP activity were measured. Additional animals were subjected to 3 hours MCA occlusion/21 hours reperfusion, and infarct size and HT were evaluated as indices of neurovascular injury. All remodeling markers including MMP-9 activity were increased in diabetes. Infarct size was smaller in minocycline-treated animals. Both metformin and minocycline reduced vascular remodeling and severity of HT in diabetes. These results provide evidence that diabetes-mediated stimulation of MMP-9 activity promotes cerebrovascular remodeling, which contributes to greater HT in diabetes. Metformin and minocycline offer vascular protection, which has important clinical implications for diabetes patients who are at a fourfold to sixfold higher risk for stroke.

Original languageEnglish (US)
Pages (from-to)1928-1938
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume30
Issue number12
DOIs
StatePublished - Dec 1 2010

    Fingerprint

Keywords

  • MMP
  • diabetes
  • hemorrhagic transformation
  • stroke
  • vascular remodeling

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this