Combination treatment of stroke with sub-therapeutic doses of Simvastatin and human umbilical cord blood cells enhances vascular remodeling and improves functional outcome

Neuroscience. 2012 Dec 27;227:223-31. doi: 10.1016/j.neuroscience.2012.09.066. Epub 2012 Oct 4.

Abstract

Human umbilical cord blood cells (HUCBCs) have been employed as a restorative treatment for experimental stroke. In this study, we investigated whether transplantation of sub-therapeutic doses of HUCBCs and Simvastatin enhances cerebral vascular remodeling after stroke. Adult male Wistar rats (n=34) were subjected to transient middle cerebral artery occlusion (MCAo) and treated with: phosphate-buffered solution (PBS, gavaged daily for 7 days); Simvastatin (0.5mg/kg, gavaged daily for 7 days); HUCBCs (1×10(6), injected once via tail vein); and combination Simvasatin with HUCBCs, starting at 24h after MCAo. There was no significant difference between Simvastatin- or HUCBC-monotherapy and MCAo-alone group. Combination treatment 24h post-stroke significantly increased the perimeter of von Willebrand factor (vWF)-positive vessels, the diameter and density of alpha smooth muscle actin (αSMA)-positive arteries, and the percentage of 5-bromodeoxyuridine (BrdU)-positive endothelial cells (ECs) in the ischemic boundary zone (IBZ) compared with MCAo-alone or HUCBC-monotherapy 14 days after MCAo (p<0.05, n=8/group); Combination treatment significantly increased the densities of vWF-vessels and αSMA-arteries as well as the densities of BrdU-ECs and BrdU-positive smooth muscle cells (SMCs) in vascular walls in the IBZ compared with Simvastatin-monotherapy. Moreover, the increased BrdU-ECs and BrdU-SMCs were significantly correlated with neurological functional outcome 14 days after MCAo. Combination treatment also significantly increased the expression of Angiopoietin-1 (Ang1), Tie2 and Occludin in the IBZ (p<0.05, n=8/group). The in vitro experiments showed that combination treatment and Ang1 significantly increased capillary-like tube formation and arterial cell migration; anti-Ang1 significantly reduced combination treatment-induced tube-formation and artery cell migration (p<0.05, n=6/group). These findings indicated that a combination of sub-therapeutic doses of Simvastatin and HUCBCs treatment of stroke increases Ang1/Tie2 and Occludin expression in the ischemic brain, amplifies endogenous angiogenesis and arteriogenesis, and enhances vascular remodeling which in concert may contribute to functional outcome after stroke.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Angiopoietins / immunology
  • Angiopoietins / metabolism
  • Animals
  • Antibodies / pharmacology
  • Anticholesteremic Agents / therapeutic use*
  • Arteries / cytology
  • Bromodeoxyuridine
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cells, Cultured
  • Disease Models, Animal
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / transplantation*
  • Humans
  • Lectins / metabolism
  • Linear Models
  • Male
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / therapy
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / physiology
  • Rats
  • Rats, Wistar
  • Simvastatin / therapeutic use*
  • Stroke / drug therapy*
  • Stroke / surgery*
  • Time Factors

Substances

  • Angiopoietins
  • Antibodies
  • Anticholesteremic Agents
  • Lectins
  • Simvastatin
  • Bromodeoxyuridine