title: Intravenous transfusion of endothelial colony-forming cells attenuates vascular degeneration after cerebral aneurysm induction.
abstract: Cerebral aneurysm (CA) rupture is a major cause of subarachnoid hemorrhage with high morbidity and mortality. Using an animal model, we examined the potential of endothelial colony-forming cells (ECFCs) transfusion on vascular degeneration after CA induction and underlying mechanisms. CA was induced in the right anterior cerebral artery-olfactory artery (ACA/OA) bifurcations in Sprague-Dawley rats with or without ECFCs transfusion. The degeneration of internal elastic lamina (IEL), media thickness and CA size were evaluated. Expression of matrix metalloproteinase-2 and 9 (MMP-2 and 9), tissue inhibitor of metalloproteinase-1 (TIMP-1), macrophage chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), nuclear factor κB (NF-κB), endothelial nitric oxide synthase (eNOS), B-cell leukemia/lymphoma-2 (Bcl-2), and inducible nitric oxide synthase (iNOS) were analyzed by quantitative real-time polymerase chain reaction. The macrophages infiltration and apoptosis of smooth muscle cells (SMCs) were examined immunohistologically. Rats in CA+ECFCs transfusion group showed a notable reduction in IEL degeneration, media thinning and CA size compared with those in CA+saline group. ECFCs transfusion inhibited the MMP-driven wall destruction by downregulating MMP-2, MMP-9 expression and upregulating TIMP-1. ECFCs transfusion dramatically decreased VCAM-1 and NF-κB expression, increased eNOS expression and caused no change in MCP-1 expression, which was accompanied by reduced macrophages infiltration. Moreover, ECFCs transfusion reversed downregulation of Bcl-2 expression and upregulation of iNOS expression, and decreased SMCs apoptosis. Collectively, these findings suggest that ECFCs transfusion confers protection against degeneration of aneurysmal wall by inhibiting inflammatory cascades and SMCs apoptosis.
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
authors.forename: Shengjie
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
authors.forename: Xintao
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
authors.forename: Dehui
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
authors.forename: Huijie
authors.initials: H
authors.lastname: Wei
authors.affiliation: Puget Sound Blood Research Institute, 1551 Eastlake Ave E, Seattle, WA 98102, USA.
authors.forename: Jingfei
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China. Electronic address: jianghope@gmail.com.
authors.forename: Rongcai
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China. Electronic address: jianningzhang@hotmail.com.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D020771:Anterior Cerebral Artery; D017209:Apoptosis / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000637:transplantation*; D002532:Intracranial Aneurysm / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D019010:Vascular Cell Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: Apoptosis; Cerebral aneurysm; Endothelial colony-forming cells; Inflammation; Macrophage; Transfusion