title: HMGB1 may act via RAGE to promote angiogenesis in the later phase after intracerebral hemorrhage.
abstract: Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote vascular remodeling. Whether HMGB1 supports angiogenesis after ICH is unclear, as are the receptors and downstream signaling pathway(s) involved. We used the rat model of collagenase-induced ICH to determine whether HMGB1 acts via the receptor for advanced glycation end-products (RAGE) to upregulate vascular endothelial growth factor (VEGF), a potent mitogen of endothelial cells and key regulator of normal and abnormal angiogenesis in the late phase of injury. At 3d after ICH induction, rats were treated with saline, ethyl pyruvate (EP) or N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). ICH induced the movement of HMGB1 from the nucleus into the cytoplasm. Levels of HMGB1 and RAGE in the ipsilateral striatum increased within a few days of induction and continued to rise for 7-14d afterward. By 14d after induction, levels of VEGF and vessel density were higher than in the Sham group. Administering EP 3 days after ICH induction prevented much of the stroke-induced increases in vessel density and in expression of HMGB1, RAGE, and VEGF. Administering FPS-ZM1 after ICH blocked much of the stroke-induced increases in vessel density and VEGF expression. Our results suggest that after ICH, HMGB1 may upregulate VEGF in the ipsilateral striatum predominantly via RAGE. Hence, targeting the HMGB1/RAGE signaling pathway may help reduce inappropriate angiogenesis after ICH.
authors: Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China.
authors: C
authors: C
authors: Lei
authors: Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China. Electronic address: zsh9@hotmail.com.
authors: S
authors: S
authors: Zhang
authors: Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China.
authors: T
authors: T
authors: Cao
authors: Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China.
authors: W
authors: W
authors: Tao
authors: Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China.
authors: M
authors: M
authors: Liu
authors: Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China. Electronic address: dragonwbtxf@hotmail.com.
authors: B
authors: B
authors: Wu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D017364:Collagenases / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011773:Pyruvates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001549:Benzamides; C572629:FPS-ZM1; D005904:Glial Fibrillary Acidic Protein; D024243:HMGB1 Protein; D011773:Pyruvates; D000067759:Receptor for Advanced Glycation End Products; D042461:Vascular Endothelial Growth Factor A; C046522:ethyl pyruvate; D017364:Collagenases
keywords: angiogenesis; high-mobility group box 1; intracerebral hemorrhage; receptor for advanced glycation end-products