脑缺血后周细胞及相关血管生成信号通路的研究进展
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摘要
周细胞与内皮细胞、星形胶质细胞以及胞外间隙共同构成血脑屏障(BBB),周细胞与内皮细胞通过各种机制通路参与多种BBB的功能调节,共同维持神经血管单元(NVU)的稳定。NVU的损伤与修复涉及诸多分子水平的信号传递。血管生成主要是内皮细胞的发生成熟和周细胞的支持黏附过程。本文主要就目前NVU缺血损伤后周细胞与内皮细胞相关的血管生成信号通路研究进行综述。
Pericytes, endothelial cells(EC), astrocytes and extracellular space together constitute the blood-brain barrier. Pericytes and EC participate in the various regulations of blood-brain barriers through many mechanisms to maintain the stability of neurovascular units(NVU). The injury and repair of NVU involve a lot of signal transduction at molecular levels, and angiogenesis is primarily about the generation and maturation of EC and the supporting adhesion process of pericytes.This article briefly reviewed EC-related angiogenesis signaling pathways in pericytes after NVU ischemic injury.
Pericytes, endothelial cells(EC), astrocytes and extracellular space together constitute the blood-brain barrier. Pericytes and EC participate in the various regulations of blood-brain barriers through many mechanisms to maintain the stability of neurovascular units(NVU). The injury and repair of NVU involve a lot of signal transduction at molecular levels, and angiogenesis is primarily about the generation and maturation of EC and the supporting adhesion process of pericytes.This article briefly reviewed EC-related angiogenesis signaling pathways in pericytes after NVU ischemic injury.
引文
[1]Hoffmann C J,Harms U,Rex A,et al.Vascular signal transducer and activator of transcription-3 promotes angiogenesis and neuroplasticity long-term after stroke[J].Circulation,2015,131(20):1772-1782.
[2]Hermann D M,Anil Z,Britta K,et al.Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia[J].Neurobiol Dis,2015,83:16-25.
[3]Dore-Duffy P.Pericytes:pluripotent cells of the blood brain barrier[J].Curr Pharm Des,2008,14(16):1581-1593.
[4]Krupinski J,Kaluza J,Kumar P,et al.Prognostic value of blood vessel density in ischaemic stroke[J].Lancet,1993,342(8873):742.
[5]Otrock Z K,Mahfouz R A,Makarem J A,et al.Understanding the biology of angiogenesis:review of the most important molecular mechanisms[J].Blood Cells Mol Dis,2007,39(2):212-220.
[6]Quittet M S,Touzani O,Sindji L,et al.Effects of mesenchymal stem cell therapy,in association with pharmacologically active microcarriers releasing VEGF,in an ischaemic stroke model in the rat[J].Acta Biomater,2015,15:77-88.
[7]Yang X,Zhu H,Ge Y,et al.Melittin enhances radiosensitivity of hypoxic head and neck squamous cell carcinoma by suppressing HIF-1α[J].Tumour Biol,2014,35(10):10443-10448.
[8]Zhang X,Lassila M,Cooper M E,et al.Retinal expression of vascular endothelial growth factor is mediated by angiotensin type 1 and type 2 receptors[J].Hypertension,2004,43(2):276.
[9]Jain R K.Molecular regulation of vessel maturation[J].Nat Med,2003,9(6):685-693.
[10]Caporali A,Martello A,Miscianinov V,et al.Contribution of pericyte paracrine regulation of the endothelium to angiogenesis[J].Pharmacol Ther,2016,171:56.
[11]Augustin H G,Gou Y K,Thurston G,et al.Control of vascular morphogenesis and homeostasis through the angiopoietinTie system[J].Nat Rev Mol Cell Biol,2009,10(3):165-177.
[12]Holger G,Matthew G,Marcus F,et al.VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia[J].J Cell Biol,2003,161(6):1163-1177.
[13]Isogai S,Lawson N D,Torrealday S,et al.Angiogenic network formation in the developing vertebrate trunk[J].Development,2003,130(21):5281-5290.
[14]M?rg?ritescu O,Pirici D,M?rg?ritescu C.VEGF expression in human brain tissue after acute ischemic stroke[J].Rom JMorphol Embryol,2011,52(4):1283-1292.
[15]Lee S C,Lee K Y,Kim Y J,et al.Serum VEGF levels in acute ischaemic strokes are correlated with long-term prognosis[J].Eur J Neurol,2010,17(1):45-51.
[16]Greenberg D A,Jin K.Vascular endothelial growth factors(VEGFs)and stroke[J].Cell Mol Life Sci,2013,70(10):1753.
[17]Zechariah A,Elali A,Doeppner T R,et al.Vascular endothelial growth factor promotes pericyte coverage of brain capillaries,improves cerebral blood flow during subsequent focal cerebral ischemia,and preserves the metabolic penumbra[J].Stroke,2013,44(6):1690-1697.
[18]Shen S W,Duan C L,Chen X H,et al.Neurogenic effect of VEGF is related to increase of astrocytes transdifferentiation into new mature neurons in rat brains after stroke[J].Neuropharmacology,2016,108:451-461.
[19]Ribatti D,Nico B,Crivellato E.The role of pericytes in angiogenesis[J].Int J Dev Biol,2011,55(3):261-268.
[20]Cristofaro B,Shi Y,Faria M,et al.Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models[J].Development,2013,140(8):1720-1729.
[21]Gale N W,Dominguez M G,Noguera I,et al.Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development[J].Proc Natl Acad Sci U S A,2004,101(45):15949-15954.--538
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[23]Ran Q,Yu Y,Fu X,et al.Activation of the Notch signaling pathway promotes neurovascular repair after traumatic brain injury[J].Neural Regener Res,2015,10(8):1258-1264.
[24]Yamamoto Y,Craggs L,Baumann M,et al.Review:molecular genetics and pathology of hereditary small vessel diseases of the brain[J].Neuropathol Appl Neurobiol,2011,37(1):94-113.
[25]王拯,张莛蔚,韩向龙.Notch信号通路调控下的血管形成[J].中国组织工程研究,2015,19(46):7498-7503.
[26]Liu J,Wang Y,Akamatsu Y,et al.Vascular remodeling after ischemic stroke:mechanisms and therapeutic potentials[J].Prog Neurobiol,2014,115(2):138-156.
[27]赵雅宁,刘文倩,牛静,等.参芎化瘀胶囊通过VEGF/Notch1信号通路改善大鼠缺血性脑卒中损伤[J].西安交通大学学报(医学版),2014,35(06):843-847.
[28]董丽,孔令蕊,王恬.Notch信号通路对免疫细胞的调节作用[J].中国生物化学与分子生物学报,2013,29(12):1106-1112.
[29]Gu A,Shively J E.Angiopoietins-1 and-2 play opposing roles in endothelial sprouting of embryoid bodies in 3D culture and their receptor Tie-2 associates with the cell-cell adhesion molecule PECAM1[J].Exp Cell Res,2011,317(15):2171.
[30]Marron M B,Singh H,Tahir T A,et al.Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2[J].J Biol Chem,2007,282(42):30509-30517.
[31]Su H,Takagawa J,Huang Y,et al.Additive effect of AAV-mediated angiopoietin-1 and VEGF expression on the therapy of infarcted heart[J].Int J Cardiol,2009,133(2):191-197.
[32]Armulik A,Abramsson A,Betsholtz C.Endothelial/pericyte interactions[J].Circ Res,2005,97(6):512-523.
[33]Fagiani E,Lorentz P,Kopfstein L,et al.Angiopoietin-1 and-2exert antagonistic functions in tumor angiogenesis,yet both induce lymph angiogenesis[J].Cancer Res,2011,71(17):5717-5727.
[34]Huang H,Bhat A,Woodnutt G,et al.Targeting the ANGPT-TIE2 pathway in malignancy[J].Nat Rev Cancer,2010,10(8):575.
[35]Zheng Q,Zhu D,Bai Y,et al.Exercise improves recovery after ischemic brain injury by inducing the expression of angiopoietin-1 and Tie-2 in rats[J].Tohoku J Exp Med,2010,224(3):221-228.
[36]Cipriani P,Marrelli A,Benedetto P D,et al.Scleroderma mesenchymal stem cells display a different phenotype from healthy controls:implications for regenerative medicine[J].Angiogenesis,2013,16(3):595-607.
[37]Armulik A,M?e M,Betsholtz C.Pericytes and the bloodbrain barrier:recent advances and implications for the delivery of CNS therapy[J].Ther Delivery,2011,2(4):419.
[38]Wilkerson B A,Argraves K M.The role of sphingosine-1-phosphate in endothelial barrier function[J].Biochim Biophys Acta Mol Cell Biol Lipids,2014,1841(10):1403-1412.
[39]Mercadopimentel M E,Runyan R B.Multiple transforming growth factor-beta isoforms and receptors function during epithelial-mesenchymal cell transformation in the embryonic heart[J].Cells Tissues Organs,2007,185(1-3):146-156.
[40]Sinha S,Hoofnagle M H,Kingston P A,et al.Transforming growth factor-beta 1 signaling contributes to development of smooth muscle cells from embryonic stem cells[J].Am J Physiol,2004,287:1560-1568.
[41]Greenberg J I,Shields Proia R L,Hla T.Emerging biology of sphingosine-1-phosphate:its role in pathogenesis and therapy[J].J Clin Invest,2015,125(4):1379.
[42]Greenberg J I,Shields D J,Barillas S G,et al.A role for VEGF as a negative regulator of pericyte function and vessel maturation[J].Nature,2008,456:809-813.
[43]Carmeliet P.Angiogenesis in life,disease and medicine[J].Nature,2005,438:932-936.
[44]Lima S,Milstien S,Spiegel S.Sphingosine and sphingosine kinase 1 involvement in endocytic membrane trafficking[J].JBiol Chem,2017,292(8):3074-3088.
[45]Lin J J,Chang T,Cai W K,et al.Post-injury administration of allicin attenuates ischemic brain injury through sphingosine kinase 2:In vivo and in vitro studies[J].Neurochem Int,2015,89:92-100.
[46]Krueger M,Bechmann I.CNS pericytes:concepts,misconceptions,and a way out[J].Glia,2010,58(1):1-10.
[47]臧妍妍,李卫红,张赛,等.TGF-β信号转导通路在缺血性脑损伤中的分子机制研究[J].云南中医学院学报,2016,39(4):94-98.
[48]孙伟,苏志强,宋丽,等.大鼠局灶性脑缺血再灌注中1-磷酸鞘氨醇受体1的表达变化[J].中风与神经疾病杂志,2011,28(2):108-110.
[49]Tanimoto T,Jin Z G,Berk B C.Transactivation of VEGF receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and eNOS[J].J Biol Chem,2002,277(45):42997-43001.
[50]Hla T.Physiological and pathological actions of sphingosine1-phosphate[J].Semin Cell Dev Biol,2004,15(5):513-520.
[51]Bazzazi H,Popel A S.Computational investigation of sphingosine kinase 1(SphK1)and calcium dependent ERK1/2 activation downstream of VEGFR2 in endothelial cells[J].PLoSComput Biol,2017,13(2):e1005332.
[52]Lee S W,Moskowitz M A,Sims J R.Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts[J].Int J Mol Med,2007,19(3):445.
[53]Walshe T E,Connell P,Cryan L,et al.Microvascular retinal endothelial and pericyte cell apoptosis in vitro:role of hedgehog and notch signaling[J].Invest Ophthalmol Visual Sci,2011,52(7):4472-4483.
[54]Song N,Huang Y,Shi H,et al.Overexpression of platelet-derived growth factor-BB increases tumor pericyte content via stromal-derived factor-1alpha/CXCR4 axis[J].Cancer Res,2009,69(15):6057-6064.
[55]蒋福林,艾冬青,官秋玥.周细胞概念及在血管形成信号转导通路研究中的进展[J].中国组织工程研究,2015,19(46):7504-7508.
[56]Bethani I,Sk?nland S S,Dikic I,et al.Spatial organization of transmembrane receptor signaling[J].EMBO J,2010,29(16):2677-2688.
[2]Hermann D M,Anil Z,Britta K,et al.Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia[J].Neurobiol Dis,2015,83:16-25.
[3]Dore-Duffy P.Pericytes:pluripotent cells of the blood brain barrier[J].Curr Pharm Des,2008,14(16):1581-1593.
[4]Krupinski J,Kaluza J,Kumar P,et al.Prognostic value of blood vessel density in ischaemic stroke[J].Lancet,1993,342(8873):742.
[5]Otrock Z K,Mahfouz R A,Makarem J A,et al.Understanding the biology of angiogenesis:review of the most important molecular mechanisms[J].Blood Cells Mol Dis,2007,39(2):212-220.
[6]Quittet M S,Touzani O,Sindji L,et al.Effects of mesenchymal stem cell therapy,in association with pharmacologically active microcarriers releasing VEGF,in an ischaemic stroke model in the rat[J].Acta Biomater,2015,15:77-88.
[7]Yang X,Zhu H,Ge Y,et al.Melittin enhances radiosensitivity of hypoxic head and neck squamous cell carcinoma by suppressing HIF-1α[J].Tumour Biol,2014,35(10):10443-10448.
[8]Zhang X,Lassila M,Cooper M E,et al.Retinal expression of vascular endothelial growth factor is mediated by angiotensin type 1 and type 2 receptors[J].Hypertension,2004,43(2):276.
[9]Jain R K.Molecular regulation of vessel maturation[J].Nat Med,2003,9(6):685-693.
[10]Caporali A,Martello A,Miscianinov V,et al.Contribution of pericyte paracrine regulation of the endothelium to angiogenesis[J].Pharmacol Ther,2016,171:56.
[11]Augustin H G,Gou Y K,Thurston G,et al.Control of vascular morphogenesis and homeostasis through the angiopoietinTie system[J].Nat Rev Mol Cell Biol,2009,10(3):165-177.
[12]Holger G,Matthew G,Marcus F,et al.VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia[J].J Cell Biol,2003,161(6):1163-1177.
[13]Isogai S,Lawson N D,Torrealday S,et al.Angiogenic network formation in the developing vertebrate trunk[J].Development,2003,130(21):5281-5290.
[14]M?rg?ritescu O,Pirici D,M?rg?ritescu C.VEGF expression in human brain tissue after acute ischemic stroke[J].Rom JMorphol Embryol,2011,52(4):1283-1292.
[15]Lee S C,Lee K Y,Kim Y J,et al.Serum VEGF levels in acute ischaemic strokes are correlated with long-term prognosis[J].Eur J Neurol,2010,17(1):45-51.
[16]Greenberg D A,Jin K.Vascular endothelial growth factors(VEGFs)and stroke[J].Cell Mol Life Sci,2013,70(10):1753.
[17]Zechariah A,Elali A,Doeppner T R,et al.Vascular endothelial growth factor promotes pericyte coverage of brain capillaries,improves cerebral blood flow during subsequent focal cerebral ischemia,and preserves the metabolic penumbra[J].Stroke,2013,44(6):1690-1697.
[18]Shen S W,Duan C L,Chen X H,et al.Neurogenic effect of VEGF is related to increase of astrocytes transdifferentiation into new mature neurons in rat brains after stroke[J].Neuropharmacology,2016,108:451-461.
[19]Ribatti D,Nico B,Crivellato E.The role of pericytes in angiogenesis[J].Int J Dev Biol,2011,55(3):261-268.
[20]Cristofaro B,Shi Y,Faria M,et al.Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models[J].Development,2013,140(8):1720-1729.
[21]Gale N W,Dominguez M G,Noguera I,et al.Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development[J].Proc Natl Acad Sci U S A,2004,101(45):15949-15954.--538
[22]Chappell J C,Mouillesseaux K P,Bautch V L.Flt-1(vascular endothelial growth factor receptor-1)is essential for the vascular endothelial growth factor-Notch feedback loop during angiogenesis[J].Arterioscler Thromb Vasc Biol,2013,33(8):1952-1959.
[23]Ran Q,Yu Y,Fu X,et al.Activation of the Notch signaling pathway promotes neurovascular repair after traumatic brain injury[J].Neural Regener Res,2015,10(8):1258-1264.
[24]Yamamoto Y,Craggs L,Baumann M,et al.Review:molecular genetics and pathology of hereditary small vessel diseases of the brain[J].Neuropathol Appl Neurobiol,2011,37(1):94-113.
[25]王拯,张莛蔚,韩向龙.Notch信号通路调控下的血管形成[J].中国组织工程研究,2015,19(46):7498-7503.
[26]Liu J,Wang Y,Akamatsu Y,et al.Vascular remodeling after ischemic stroke:mechanisms and therapeutic potentials[J].Prog Neurobiol,2014,115(2):138-156.
[27]赵雅宁,刘文倩,牛静,等.参芎化瘀胶囊通过VEGF/Notch1信号通路改善大鼠缺血性脑卒中损伤[J].西安交通大学学报(医学版),2014,35(06):843-847.
[28]董丽,孔令蕊,王恬.Notch信号通路对免疫细胞的调节作用[J].中国生物化学与分子生物学报,2013,29(12):1106-1112.
[29]Gu A,Shively J E.Angiopoietins-1 and-2 play opposing roles in endothelial sprouting of embryoid bodies in 3D culture and their receptor Tie-2 associates with the cell-cell adhesion molecule PECAM1[J].Exp Cell Res,2011,317(15):2171.
[30]Marron M B,Singh H,Tahir T A,et al.Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2[J].J Biol Chem,2007,282(42):30509-30517.
[31]Su H,Takagawa J,Huang Y,et al.Additive effect of AAV-mediated angiopoietin-1 and VEGF expression on the therapy of infarcted heart[J].Int J Cardiol,2009,133(2):191-197.
[32]Armulik A,Abramsson A,Betsholtz C.Endothelial/pericyte interactions[J].Circ Res,2005,97(6):512-523.
[33]Fagiani E,Lorentz P,Kopfstein L,et al.Angiopoietin-1 and-2exert antagonistic functions in tumor angiogenesis,yet both induce lymph angiogenesis[J].Cancer Res,2011,71(17):5717-5727.
[34]Huang H,Bhat A,Woodnutt G,et al.Targeting the ANGPT-TIE2 pathway in malignancy[J].Nat Rev Cancer,2010,10(8):575.
[35]Zheng Q,Zhu D,Bai Y,et al.Exercise improves recovery after ischemic brain injury by inducing the expression of angiopoietin-1 and Tie-2 in rats[J].Tohoku J Exp Med,2010,224(3):221-228.
[36]Cipriani P,Marrelli A,Benedetto P D,et al.Scleroderma mesenchymal stem cells display a different phenotype from healthy controls:implications for regenerative medicine[J].Angiogenesis,2013,16(3):595-607.
[37]Armulik A,M?e M,Betsholtz C.Pericytes and the bloodbrain barrier:recent advances and implications for the delivery of CNS therapy[J].Ther Delivery,2011,2(4):419.
[38]Wilkerson B A,Argraves K M.The role of sphingosine-1-phosphate in endothelial barrier function[J].Biochim Biophys Acta Mol Cell Biol Lipids,2014,1841(10):1403-1412.
[39]Mercadopimentel M E,Runyan R B.Multiple transforming growth factor-beta isoforms and receptors function during epithelial-mesenchymal cell transformation in the embryonic heart[J].Cells Tissues Organs,2007,185(1-3):146-156.
[40]Sinha S,Hoofnagle M H,Kingston P A,et al.Transforming growth factor-beta 1 signaling contributes to development of smooth muscle cells from embryonic stem cells[J].Am J Physiol,2004,287:1560-1568.
[41]Greenberg J I,Shields Proia R L,Hla T.Emerging biology of sphingosine-1-phosphate:its role in pathogenesis and therapy[J].J Clin Invest,2015,125(4):1379.
[42]Greenberg J I,Shields D J,Barillas S G,et al.A role for VEGF as a negative regulator of pericyte function and vessel maturation[J].Nature,2008,456:809-813.
[43]Carmeliet P.Angiogenesis in life,disease and medicine[J].Nature,2005,438:932-936.
[44]Lima S,Milstien S,Spiegel S.Sphingosine and sphingosine kinase 1 involvement in endocytic membrane trafficking[J].JBiol Chem,2017,292(8):3074-3088.
[45]Lin J J,Chang T,Cai W K,et al.Post-injury administration of allicin attenuates ischemic brain injury through sphingosine kinase 2:In vivo and in vitro studies[J].Neurochem Int,2015,89:92-100.
[46]Krueger M,Bechmann I.CNS pericytes:concepts,misconceptions,and a way out[J].Glia,2010,58(1):1-10.
[47]臧妍妍,李卫红,张赛,等.TGF-β信号转导通路在缺血性脑损伤中的分子机制研究[J].云南中医学院学报,2016,39(4):94-98.
[48]孙伟,苏志强,宋丽,等.大鼠局灶性脑缺血再灌注中1-磷酸鞘氨醇受体1的表达变化[J].中风与神经疾病杂志,2011,28(2):108-110.
[49]Tanimoto T,Jin Z G,Berk B C.Transactivation of VEGF receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and eNOS[J].J Biol Chem,2002,277(45):42997-43001.
[50]Hla T.Physiological and pathological actions of sphingosine1-phosphate[J].Semin Cell Dev Biol,2004,15(5):513-520.
[51]Bazzazi H,Popel A S.Computational investigation of sphingosine kinase 1(SphK1)and calcium dependent ERK1/2 activation downstream of VEGFR2 in endothelial cells[J].PLoSComput Biol,2017,13(2):e1005332.
[52]Lee S W,Moskowitz M A,Sims J R.Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts[J].Int J Mol Med,2007,19(3):445.
[53]Walshe T E,Connell P,Cryan L,et al.Microvascular retinal endothelial and pericyte cell apoptosis in vitro:role of hedgehog and notch signaling[J].Invest Ophthalmol Visual Sci,2011,52(7):4472-4483.
[54]Song N,Huang Y,Shi H,et al.Overexpression of platelet-derived growth factor-BB increases tumor pericyte content via stromal-derived factor-1alpha/CXCR4 axis[J].Cancer Res,2009,69(15):6057-6064.
[55]蒋福林,艾冬青,官秋玥.周细胞概念及在血管形成信号转导通路研究中的进展[J].中国组织工程研究,2015,19(46):7504-7508.
[56]Bethani I,Sk?nland S S,Dikic I,et al.Spatial organization of transmembrane receptor signaling[J].EMBO J,2010,29(16):2677-2688.