COMBINATION TREATMENT OF STROKE WITH SUB-THERAPEUTIC DOSES OF SI M VAST ATI N AND HUMAN UMBILICAL CORD BLOOD CELLS ENHANCES VASCULAR REMODELING AND IMPROVES FUNCTIONAL OUTCOME

摘要

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 (0.5 mg/kg, gavaged daily for 7 days); HUCBCs (1 x 106, injected once via tail vein); and combination Simva-satin with HUCBCs, starting at 24 h after MCAo. There was no significant difference between Simvastatin- or HUCBC-monotherapy and MCAo-alone group. Combination treatment 24 h post-stroke significantly increased the perimeter of von Willebrand factor (vWF)-positive vessels, the diameter and density of alpha smooth muscle actin (ocSMA)-posi-tive arteries, and the percentage of 5-bromodeoxyuridine (BrdU)-positive endothelial cells (ECs) in the ischemic boundary zone (lBZ) 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 aSMA-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.