title: Combination treatment of stroke with sub-therapeutic doses of Simvastatin and human umbilical cord blood cells enhances vascular remodeling and improves functional outcome.
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.
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: X
authors.initials: X
authors.lastname: Cui
authors.forename: M
authors.initials: M
authors.lastname: Chopp
authors.forename: A
authors.initials: A
authors.lastname: Zacharek
authors.forename: J
authors.initials: J
authors.lastname: Dai
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Yan
authors.forename: R
authors.initials: R
authors.lastname: Ning
authors.forename: C
authors.initials: C
authors.lastname: Roberts
authors.forename: A
authors.initials: A
authors.lastname: Shehadah
authors.forename: N
authors.initials: N
authors.lastname: Kuzmin-Nichols
authors.forename: C D
authors.initials: CD
authors.lastname: Sanberg
authors.forename: J
authors.initials: J
authors.lastname: Chen
mesh_terms: D000704:Analysis of Variance; D042682:Angiopoietins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001158:Arteries / Q000166:cytology; D001973:Bromodeoxyuridine; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000637:transplantation*; D006801:Humans; D037102:Lectins / Q000378:metabolism; D016014:Linear Models; D008297:Male; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy* / Q000601:surgery*; D013997:Time Factors
chemical_list: D042682:Angiopoietins; D000906:Antibodies; D000924:Anticholesteremic Agents; D037102:Lectins; D019821:Simvastatin; D001973:Bromodeoxyuridine