혈관내피세포의 이동에 미치는 Hepatocyte Growth Factor의 영향

Effect of Hepatocyte Growth Factor on the Migration of Human Umbilical Vein Endothelial Cells

  • 오인숙 (전북대학교 자연과학대학 생물과학부) ;
  • 소상섭 (전북대학교 자연과학대학 생물과학부) ;
  • 김환규 (전북대학교 자연과학대학 생물과학부)
  • 발행 : 2003.12.01

초록

HGF는 내피세포의 증식 및 이동을 일으키는 강력한 혈관 신생 유도인자 및 생존인자로서 작용한다고 알려져 있다. 본 연구에서는 HUVECs 세포를 이용하여 내피세포의 이동 및 단백질분해효소의 분비에 미치는 HGF의 효과를 확인하였다. 그 곁과, HGF 처리 (10ng/$m\ell$)에 의해 HUVECs 세포의 이동이 약 3.3배 촉진되어, HGF가 HUVECs 세포에서 강력한 이동 유도인자라는 사실을 확인하였다. 내피세포의 이동에 관여할 것이라 여겨지는 MMPs, TIMPs 및 플라스민의 분비에 미치는 HGF의 효과를 관찰한 결과, HGF에 의해 MMP-2 및 MMP-3의 분비양이 각각 3.3배와 6.1배씩 증가되었다. HGF에 의한 TIMPs 분비효과를 관찰한 결과, TIMP-1은 대조군에 비해 약 1.8배 분비가 증가되었으나, TIMP-2는 대조군에 비해 약 3.1배 분비가 억제되었다. 또한, 광범위 MMPs-억제제인 BB-94 (20ng/$m\ell$) 및 플라스민 억제제인 $\alpha$$_2$-antiplasmin (100mU)을 처리했을 때, HGF에 의해 유도된 혈관내피세포의 이동이 거의 완벽하게 억제되었다. 결론적으로, HGF는 HUVECs 세포에서 MMP-2, MMP-3, MMP-9, TIMP-1 및 플라스민의 분비 증가를 일으켰으며, HGF에 의해 분비가 증가 된 단백질분해효소에 의해 세포외기질 및 기저막 단백질로의 혈관내피세포의 이동이 촉진되고, 결과적으로 혈관신생을 유도할 것이라 사료된다.

Hepatocyte growth factor (HGF) is a mesenchymal-derived cytokine. It exerts a motogenic effect on various target cells, which is displayed either by cell scattering, locomotion, and migration during the wound repair process of cultured cells, or invasiveness through the extracellular matrix, in vitro. Although it is known that HGF influences the motogenic effect of endothelial cells, the precise effects of HGF during migration are still poorly understood. To elucidate the role of HGF in endothelial cell migration, the effect of HGF on endothelial cell migration and MMPs and plasmin production were studied. We found that HGF induces the migration of cultured endothelial cells through increased MMPs and plasmin secretion.

키워드

참고문헌

  1. Nature v.386 Machanisms of angiogenesis Risau,W. https://doi.org/10.1038/386671a0
  2. Cell v.72 High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis Millauer,B.;S.Wizigmann-Voos;H.Schnurch;R.Martinez;N.P.Moller;W.Risau;A.Ullrich https://doi.org/10.1016/0092-8674(93)90573-9
  3. Science v.264 Requierment of vascular integrin alpha v beta 3 for angiogenesis Brooks,P.C.;R.A.Clark;D.A.Cheresh https://doi.org/10.1126/science.7512751
  4. Nat. Cell Biol. v.2 Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis Bergers,G.;R.Brekken;G.McMahon;T.H.Vu;T.Itoh;K.Tamaki;K.Tanzawa;P.Thorpe;S.Itohara;Z.Werbm;D.Hanahanm https://doi.org/10.1038/35036374
  5. Proc. Natl. Acad. Sci. v.97 Impaired cendochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase Ⅰ Zhou,Z.;S.S.Apte;R.Soininen;R.Cao;G.Y.Baaklimi;R.W.Rauser;J.Wang;Y.Cao;K.Tryggvason https://doi.org/10.1073/pnas.060037197
  6. Thromb. Haemost. v.86 Extracellular proteolysis and angiogenesis Pepper,M.S. https://doi.org/10.1055/s-0037-1616232
  7. Chem, Biol. v.3 Matrix mtealloproteinases and the development of cancer Coussens,L.M.;Z.Werb https://doi.org/10.1016/S1074-5521(96)90178-7
  8. J. Clin. Oncol. v.18 Matrix metalloproteinases: biologic activity and clinical implications Nelson,A.R.;B.Fingleton;M.L.Rothenberg;L.M.Matrisian https://doi.org/10.1200/JCO.2000.18.5.1135
  9. Nat. Rev. Cancer v.2 Strategies for MMP inhibition in cancer. innovations for post-trial era Overall,C.M.;C.Lopez-Otin https://doi.org/10.1038/nrc884
  10. Matrix metalloproteinases The matrix metalloproteinase family Frederick,J.;J.F.Jr.Woessner;W.C.Parks(ed.);R.P.Mecham(ed.) https://doi.org/10.1016/B978-012545090-4/50002-1
  11. BioAssays v.14 The matrix-degrading metalloproteinases Martrisian,L.M. https://doi.org/10.1002/bies.950140705
  12. Matrix metalloproteinases 72kDa gelatinase(gelatinase A): structure, activation, regulation, and substrate specificity Anita,E.Y.;A.N.Murphy;W.G.Stetler-Stevenson;W.C.Parks(ed.);R.P.Mecham(ed.) https://doi.org/10.1016/B978-012545090-4/50005-7
  13. Cell v.64 Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation Liotta,L.A.;P.S.Steeg;W.G.Stetler-Stevenson https://doi.org/10.1016/0092-8674(91)90642-C
  14. Annu. Rev. Cell. Biol. v.9 Tumor cell interactions with the extracellular matrix during invasion and metastasis Stetler-Stevenson,W.G.;S.Azanvoorian;A.Liotta https://doi.org/10.1146/annurev.cb.09.110193.002545
  15. J. Biol. Chem. v.378 Activation mechanisms of matrix metalloproteinases Nagase,H.
  16. Biochem. Biophys. Acta. v.1079 Tissue inhibitor of metalloproteinase-2 inhibits the activation of 72 kDa progelatinase by fibroblast membranes Ward,R.V.;S.J.Atkinson;P.M.Slocombe;A.J.Docherty;J.J.Reynolds;G.Murphy https://doi.org/10.1016/0167-4838(91)90132-J
  17. Biochem. Biophys. Res. Commun. v.269 Lipopolysaccharide activates matrix metalloproteinase-2 in endothelial cells through an NF-kB-dependent pathway Kim,H.G.;G.Y.Koh https://doi.org/10.1006/bbrc.2000.2308
  18. Biochem. Biophys. Res. Commun. v.179 Hepatocyte growth factor modulates migration and proliferation of human microvascular endothelial cells in culture Morimoto,A.;K.Okamura;R.Hamanaka;Y.Sato;N.Shima;K.Higashio;M.Kuwano https://doi.org/10.1016/0006-291X(91)91924-2
  19. J. Cell Biol. v.119 Hepatocyte growth factor is p potent angiogenic factor which stimulates endothelial cell motility and growth Bussolino,F.;M.F.Di Renzo;M.Aiche;E.Bocchietoo;M.Olivero;L.Naldini;G.Gaudino;L.Tamagnone;A.Coffer;P.M.Comoglio https://doi.org/10.1083/jcb.119.3.629
  20. Proc. Natl. Acad. Sci. v.90 Scatter factor induces blood vessel formation in vivo Grant,D.S.;H.K.Kleinman;I.D.Goldberg;M.Bhargava;B.J.Nickoloff;J.l.Kinsella;P.Polverini;E.M.Rosen https://doi.org/10.1073/pnas.90.5.1937
  21. Ciba Found Symp. v.323 HGF/SF in angiogenesis Rosen,E.m.;K.Lamszus;J.Laterra;P.J.Polverini;J.S.Rubin;I.D.Goldberg
  22. Biochem. Biophys. Res. Commun. v.220 Autocrine-paracrine effects of overexpression of hepatocyte growth factor gene on growth of endothelial cells Hayashi,S.;R.Morishita;J.Higaki;M.Aoki;A.Moriguchi;I.Kida;S.Yoshiki;K.Matsumoto;T.Nakamura;Y.Kaneda;T.Ogihara https://doi.org/10.1006/bbrc.1996.0440
  23. EXS v.79 Regulation of angiogenesis by scatter factor Rosen,E.M.;I.D.Goldberg
  24. Arterioscler. Thromb. Vasc. Biol. v.15 In vivo activation of met tyrosine kinase by heterodimeric hepatocyte growth factor molecule promotes angiogenesis Silvagno,F.;A.Follenzi;M.Arese;M.Prat;E.Giraudo;G.Gaudino;G.Camussi;P.M.Comoglio;F.Bussolino https://doi.org/10.1161/01.ATV.15.11.1857
  25. Circulation v.97 Potentiated angiogenic effect of scatter factor/heapatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis Belle,V.E.;B.Witzenbichler;D.Chen;M.Silver;L.Chang;R.Schwall;J.M.Isner https://doi.org/10.1161/01.CIR.97.4.381
  26. FEBS Lett. v.448 Angiopoietin-1 is an apoptosis survival factor for endothelial cells Kwak,H.J.;J.N.So;S.J.Lee;I.kim;G.Y.Koh https://doi.org/10.1016/S0014-5793(99)00378-6
  27. Circ. Res. v.86 Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion Kim,I.;H.G.Kim;S.O.Moon;S.W.Chae;J.N.So;K.N.Koh;B.C.Ahn;G.Y.Koh https://doi.org/10.1161/01.RES.86.9.952
  28. Mol. Biol. Cell v.4 Basic fibroblast growth factor modulates integrin expression in microvascular endothelial cells Kleim,S.;F.G.Giancotti;M.presta;S.A.Albelda;C.A.Buck;D.B.Rifkin https://doi.org/10.1091/mbc.4.10.973
  29. Placenta v.24 Factors regulating trophoblast migration and invasiveness: possible derangements contributing to pre-eclampsia and fetal injury Lala,P.K.;C.Chakraborty https://doi.org/10.1016/S0143-4004(03)00063-8
  30. Exp. Cell Res. v.288 Hepatocyte growth factor enhances adhesion of breast cancer cells to endothelial cells in vitro through up-regulation of CD44 Mine,S.;T.Fujisaki;C.Kawahara;T.Tabata;T.Iida;M.Yasuda;T.Yoneda;Y.Tanaka https://doi.org/10.1016/S0014-4827(03)00184-8
  31. Blood v.101 HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro Ding,S.;T.Merkulova-Rainon;Z.C.Han;G.Tobelem https://doi.org/10.1182/blood-2002-06-1731
  32. J. Clin. Invest. v.103 Matrix metalloproteinases in angiogenesis : a moving target for therapeutic intervention Stetler-Stevenson,W.G. https://doi.org/10.1172/JCI6870
  33. J. Biol. Chem. v.274 Matrix metalloproteinases Nagase,H.;J.F.Jr.Woessner https://doi.org/10.1074/jbc.274.31.21491
  34. Curr. Opin. Hematol. v.2 Changing concepts in fibrinolysis Hajjar,K.A. https://doi.org/10.1097/00062752-199502050-00004