title: Buyang huanwu decoction promotes angiogenesis via vascular endothelial growth factor receptor-2 activation through the PI3K/Akt pathway in a mouse model of intracerebral hemorrhage.
abstract: BACKGROUND
  Intracerebral hemorrhage (ICH) is a fatal subtype of stroke that lacks effective treatments. Angiogenesis following ICH is an important response mediating brain recovery and repair. Phosphorylation of vascular endothelial growth factor receptor 2 (pVEGFR2) via PI3K/Akt signaling plays a key role in mediating cellular processes involved in repair, such as mitogenesis, angiogenesis, and vascular permeability. This study aimed to investigate the potential effects of Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine formula, on angiogenesis by VEGFR2 activation through the phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway in a mouse model of ICH.
  
  
  METHODS
  Adult male Kunming mice (n = 50) were randomly assigned into sham and ICH-operated groups and treated with one of the followings SU5416 (VEGFR2 inhibitor), BYHWT and BYHWT + SU5416. ICH was induced in mice by injecting collagenase (type VII) into the right globus pallidus of the mouse brain. BYHWD (4.36 g/kg) was administrated in mice by intragastric infusion. Neurological function was evaluated in mice by a modified Neurological Severity Scores (mNSS) as well as corner turn and foot-fault tests. Angiogenesis was examined by intraperitoneal injection of 5-bromodeoxyuridine (BrdU) in mice to quantify new brain vessel growth. SU5416 treatment and assessment of VEGFR2 phosphorylation as well as alterations in PI3K/Akt signaling were performed to determine whether the effect of BYHWD on angiogenesis was partly mediated by phosphorylation of VEGFR2 via the PI3K/Akt signaling pathway.
  
  
  RESULTS
  We show that BYHWD treated mice exhibited (i) significantly better recovery from neurological dysfunction, (ii) increased BrdU(+) nuclei in vWF(+) dilated brain vessels and (iii) higher VEGFR2 phosphorylation immunoreactivity in brain microvessels (P <0.05), (iv) higher expression of PI3K and pAkt at the protein level (P <0.05) when compared to untreated ICH mice. These beneficial effects were reversed by SU5416 (P <0.05).
  
  
  CONCLUSIONS
  BYHWD promoted neurological recovery and angiogenesis after ICH in mice by enhancing VEGFR2 phosphorylation through the PI3K/Akt signaling pathway.
authors.affiliation: Institute of integrative medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. cuihanjin@csu.edu.cn.|Key Lab of Chinese Gan of SATCM, Changsha, 410008, Hunan, China. cuihanjin@csu.edu.cn.
authors.forename: Han-Jin
authors.initials: HJ
authors.lastname: Cui
authors.affiliation: Institute of neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. mulingxiaoren@163.com.|Key Lab of Chinese Gan of SATCM, Changsha, 410008, Hunan, China. mulingxiaoren@163.com.
authors.forename: A-Li
authors.initials: AL
authors.lastname: Yang
authors.affiliation: Key Lab of Chinese Gan of SATCM, Changsha, 410008, Hunan, China. zhouhuajun02@126.com.|Institute of Neurology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, 443003, Hubei, China. zhouhuajun02@126.com.
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Zhou
authors.affiliation: Institute of integrative medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. cong010101@gmail.com.|Key Lab of Chinese Gan of SATCM, Changsha, 410008, Hunan, China. cong010101@gmail.com.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of integrative medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. luojk4314131@163.com.|Key Lab of Chinese Gan of SATCM, Changsha, 410008, Hunan, China. luojk4314131@163.com.
authors.forename: Jie-Kun
authors.initials: JK
authors.lastname: Luo
authors.affiliation: Key Lab of Chinese Gan of SATCM, Changsha, 410008, Hunan, China. linyuan3454@126.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of integrative medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. 737700342@qq.com.|Key Lab of Chinese Gan of SATCM, Changsha, 410008, Hunan, China. 737700342@qq.com.
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Zong
authors.affiliation: Institute of integrative medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. falcontang@126.com.|Key Lab of Chinese Gan of SATCM, Changsha, 410008, Hunan, China. falcontang@126.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Tang
mesh_terms: D000818:Animals; D027883:Astragalus Plant; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D049109:Cell Proliferation; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D008517:Phytotherapy; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D004365:Drugs, Chinese Herbal; D042461:Vascular Endothelial Growth Factor A; C460102:buyang huanwu; D019869:Phosphatidylinositol 3-Kinases; D058539:Phosphatidylinositol 3-Kinase; D040301:Vascular Endothelial Growth Factor Receptor-2