HGF and VEGF: A Dynamic Duo
2005; Lippincott Williams & Wilkins; Volume: 96; Issue: 3 Linguagem: Inglês
10.1161/01.res.0000157575.66295.e0
ISSN1524-4571
Autores Tópico(s)Platelet Disorders and Treatments
ResumoHomeCirculation ResearchVol. 96, No. 3HGF and VEGF: A Dynamic Duo Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHGF and VEGF: A Dynamic Duo Mary E. Gerritsen Mary E. GerritsenMary E. Gerritsen From the Department of Molecular Pharmacology, Exelixis, South San Francisco, Calif. Originally published18 Feb 2005https://doi.org/10.1161/01.RES.0000157575.66295.e0Circulation Research. 2005;96:272–273The potent, proangiogenic effects of vascular endothelial growth factor (VEGF) have been the focus of many strategies to promote therapeutic angiogenesis. However, the dose-limiting proinflammatory side effects of VEGF (eg, increased vascular permeability, leukocyte adhesion, upregulated adhesion molecule expression) have raised concerns about the clinical utility of VEGF.1–4 Recently, combinations of VEGF with other growth factors (such as with angiopoeitin-1) have been tested as alternative strategies to promote new vessel growth and limit the edema and inflammation associated with VEGF.5Hepatocyte growth factor (HGF; also known as scatter factor) is a large multidomain protein structurally similar to plasminogen. The receptor for HGF is c-met, a disulphide linked heterodimer with tyrosine kinase activity. HGF is a potent endothelial mitogen, motogen, and morphogen,6,7 although in contrast to VEGF these effects are not limited to endothelial cells. HGF is induced in skeletal and cardiac muscle after ischemic injury,8,9 and HGF and its receptor c-met are often overexpressed in various tumors.10 Administration of HGF, either as a protein or incorporated into an adenoviral vector, has been shown to promote angiogenesis without increased vascular permeability or inflammation.11–17Combining HGF and VEGF results in a much more robust endothelial proliferative response and chemotactic response than either growth factor alone.18,19 In three-dimensional type I collagen gels, neither HGF nor VEGF alone are sufficient to induce human endothelial cell survival and tubulogenesis, yet the combination of the two growth factors will support these responses.19 In vivo studies also suggest that combining HGF and VEGF also induces a more robust angiogenic response.18,19Early studies of the proangiogenic actions of HGF attributed the effects of HGF to the induction of VEGF. Van Belle and coworkers suggested that HGF induced VEGF production by surrounding smooth muscle cells.18 Wojta et al20 and Gille and coworkers21 observed that HGF increased the expression of keratinocyte-derived VEGF, and suggested that HGF might induce angiogenesis by a paracrine mechanism. However, other studies suggested that the proangiogenic effects of HGF were independent of VEGF.22 A recent gene expression profiling study clearly demonstrated that HGF and VEGF signal through discrete pathways in vascular endothelial cells, and moreover, the combination of the two growth factors synergistically induces a number of genes involved in the regulation of the cell cycle.23In this issue of Circulation Research, Min and coworkers provide new insights into the potential of growth factor combinations for therapeutic angiogenesis.24 These authors report that HGF does not alter leukocyte adhesion to endothelial cells and, moreover, markedly reduces the increase in leukocyte adhesion and adhesion molecule expression stimulated by VEGF. Mechanistically, this effect appeared to be mediated by an HGF suppression of VEGF-induced NF-κB signaling. In vivo, HGF decreased VEGF-elicited leukocyte recruitment in a delayed type hypersensitivity model, whereas HGF/VEGF cotreatment markedly increased vascular density compared with either growth factor alone. This study clearly demonstrates that further study of the interactions of HGF and VEGF is warranted. Using this dynamic duo of growth factors to stimulate new vessel growth without the complications of inflammation and edema offers an exciting new direction for therapeutic angiogenesis.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Mary E. Gerritsen, Department of Molecular Pharmacology, Exelixis, 170 Harbor WAY PO Box 511, South San Francisco, CA 94083. E-mail [email protected] References 1 Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K, Isner JM. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation. 1998; 97: 1114–1123.CrossrefMedlineGoogle Scholar2 Baumgartner I, Rauh G, Pieczek A, Wuensch D, Magner M, Kearney M, Schainfeld R, Isner JM. Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor. Ann Intern Med. 2000; 132: 880–884.CrossrefMedlineGoogle Scholar3 Detmar M, Brown LF, Schon MP, Elicker BM, Velasco P, Richard L, Fukumura D, Monsky W, Claffey KP, Jain RK. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol. 1998; 111: 1–6.CrossrefMedlineGoogle Scholar4 Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J Biol Chem. 2001; 276: 7614–7620.CrossrefMedlineGoogle Scholar5 Thurston G. Complementary actions of VEGF and angiopoietin-1 on blood vessel growth and leakage. J Anat. 2002; 200: 575–580.CrossrefMedlineGoogle Scholar6 Morimoto A, Okamura K, Hamanaka R, Sato Y, Shima N, Higashio K, Kuwano M. Hepatocyte growth factor modulates migration and proliferation of human microvascular endothelial cells in culture. Biochem Biophys Res Commun. 1991; 179: 1042–1049.CrossrefMedlineGoogle Scholar7 Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A, Comoglio PM. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol. 1992; 119: 629–641.CrossrefMedlineGoogle Scholar8 Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S. Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and reperfusion in a rat model. Circulation. 1997; 95: 2552–2558.CrossrefMedlineGoogle Scholar9 Zlot C, Ingle G, Hongo J, Yang S, Sheng Z, Schwall R, Paoni N, Wang F, Peale FV Jr, Gerritsen ME. Stanniocalcin 1 is an autocrine modulator of endothelial angiogenic responses to hepatocyte growth factor. J Biol Chem. 2003; 278: 47654–47659.CrossrefMedlineGoogle Scholar10 Ma P, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003; 22: 309–325.CrossrefMedlineGoogle Scholar11 Taniyama Y, Morishita R, Hiraoka K, Aoki M, Nakagami H, Yamasaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model: molecular mechanisms of delayed angiogenesis in diabetes. Circulation. 2001; 104: 2344–2350.CrossrefMedlineGoogle Scholar12 Aoki M, Morishita R, Taniyama Y, Kaneda Y, Ogihara T. Therapeutic angiogenesis induced by hepatocyte growth factor: potential gene therapy for ischemic diseases. J Atheroscler Thromb. 2000; 7: 71–76.CrossrefMedlineGoogle Scholar13 Taniyama Y, Morishita R, Aoki M, Nakagami H, Yamamoto K, Yamazaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease. Gene Ther. 2001; 8: 181–189.CrossrefMedlineGoogle Scholar14 Morishita R, Nakamura S, Hayashi S, Taniyama Y, Moriguchi A, Nagano T, Taiji M, Noguchi H, Takeshita S, Matsumoto K, Nakamura T, Higaki J, Ogihara T. Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension. 1999; 33: 1379–1384.CrossrefMedlineGoogle Scholar15 Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J, Sawa Y, Matsuda H, Kaneda Y, Ogihara T. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension. 2004; 44: 203–209.LinkGoogle Scholar16 Aoki M, Morishita R, Taniyama Y, Kida I, Moriguchi A, Matsumoto K, Nakamura T, Kaneda Y, Higaki J, Ogihara T. Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets. Gene Ther. 2000; 7: 417–427.CrossrefMedlineGoogle Scholar17 Shimamura M, Sato N, Oshima K, Aoki M, Kurinami H, Waguri S, Uchiyama Y, Ogihara T, Kaneda Y, Morishita R. Novel therapeutic strategy to treat brain ischemia: overexpression of hepatocyte growth factor gene reduced ischemic injury without cerebral edema in rat model. Circulation. 2004; 109: 424–431.LinkGoogle Scholar18 Van Belle E, Witzenbichler B, Chen D, Silver M, Chang L, Schwall R, Isner JM. Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. Circulation. 1998; 97: 381–390.CrossrefMedlineGoogle Scholar19 Xin X, Yang S, Ingle G, Zlot C, Rangell L, Kowalski J, Schwall R, Ferrara N, Gerritsen ME. Hepatocyte growth factor enhances vascular endothelial growth factor-induced angiogenesis in vitro and in vivo. Am J Pathol. 2001; 158: 1111–1120.CrossrefMedlineGoogle Scholar20 Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, Mildner M, Weninger W, Nakamura T, Tschachler E, Binder BR. Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Lab Invest. 1999; 79: 427–438.MedlineGoogle Scholar21 Gille J, Khalik M, Konig V, Kaufmann R. Hepatocyte growth factor/scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes. J Invest Dermatol. 1998; 111: 1160–1165.CrossrefMedlineGoogle Scholar22 Sengupta S, Gherardi E, Sellers LA, Wood JM, Sasisekharan R, Fan TP. Hepatocyte growth factor/scatter factor can induce angiogenesis independently of vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 2003; 23: 69–75.LinkGoogle Scholar23 Gerritsen ME, Tomlinson JE, Zlot C, Ziman M, Hwang S. Using gene expression profiling to identify the molecular basis of the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells. Br J Pharmacol. 2003; 140: 595–610.CrossrefMedlineGoogle Scholar24 Min J-K, Lee Y-M, Kim JH, Kim Y-M, Kim SW, Lee S-Y, Gho YS, Oh GT, Kwon Y-G. Hepatocyte growth factor suppresses VEGF-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-kappaB pathway. Circ Res. 2005; 96: 300–307.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Liu C, Han J, Marcelina O, Nugrahaningrum D, Huang S, Zou M, Wang G, Miyagishi M, He Y, Wu S and Kasim V (2021) Discovery of Salidroside-Derivated Glycoside Analogues as Novel Angiogenesis Agents to Treat Diabetic Hind Limb Ischemia, Journal of Medicinal Chemistry, 10.1021/acs.jmedchem.1c00947, 65:1, (135-162), Online publication date: 13-Jan-2022. Cannatà A, Ali H, Sinagra G and Giacca M (2020) Gene Therapy for the Heart Lessons Learned and Future Perspectives, Circulation Research, 126:10, (1394-1414), Online publication date: 8-May-2020. Thewke D, Kou J, Fulmer M and Xie Q (2018) The HGF/MET Signaling and Therapeutics in Cancer Regulation of Signal Transduction in Human Cell Research, 10.1007/978-981-10-7296-3_8, (155-181), . Costa M, McDevitt T, Cabral J, da Silva C and Ferreira F (2017) Tridimensional configurations of human mesenchymal stem/stromal cells to enhance cell paracrine potential towards wound healing processes, Journal of Biotechnology, 10.1016/j.jbiotec.2017.09.020, 262, (28-39), Online publication date: 1-Nov-2017. O'Neill H, Herron C, Hastings C, Deckers R, Lopez Noriega A, Kelly H, Hennink W, McDonnell C, O'Brien F, Ruiz-Hernández E and Duffy G (2017) A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents, Acta Biomaterialia, 10.1016/j.actbio.2016.10.001, 48, (110-119), Online publication date: 1-Jan-2017. Zheng Y, Sun Y, Yu X, Shao Y, Zhang P, Dai G and Fu J (2016) Angiogenesis in Liquid Tumors: An In Vitro Assay for Leukemic‐Cell‐Induced Bone Marrow Angiogenesis, Advanced Healthcare Materials, 10.1002/adhm.201501007, 5:9, (1014-1024), Online publication date: 1-May-2016. Amuzescu B, Istrate B and Mubagwa K (2016) Impact of Cellular Mechanisms of Ischemia on CABG Failure Coronary Graft Failure, 10.1007/978-3-319-26515-5_31, (351-391), . Awada H, Hwang M and Wang Y (2016) Towards comprehensive cardiac repair and regeneration after myocardial infarction: Aspects to consider and proteins to deliver, Biomaterials, 10.1016/j.biomaterials.2015.12.025, 82, (94-112), Online publication date: 1-Mar-2016. Mastri M, Shah Z, Hsieh K, Wang X, Wooldridge B, Martin S, Suzuki G and Lee T (2014) Secreted Frizzled-related protein 2 as a target in antifibrotic therapeutic intervention, American Journal of Physiology-Cell Physiology, 10.1152/ajpcell.00238.2013, 306:6, (C531-C539), Online publication date: 15-Mar-2014. Chade A, Stewart N and Peavy P (2014) Disparate effects of single endothelin-A and -B receptor blocker therapy on the progression of renal injury in advanced renovascular disease, Kidney International, 10.1038/ki.2013.477, 85:4, (833-844), Online publication date: 1-Apr-2014. Stewart N and Chade A (2013) Renoprotective effects of hepatocyte growth factor in the stenotic kidney, American Journal of Physiology-Renal Physiology, 10.1152/ajprenal.00504.2012, 304:6, (F625-F633), Online publication date: 15-Mar-2013. Lee E, Park H, Jeon H, Kim H and Chang M (2013) Potentiated therapeutic angiogenesis by primed human mesenchymal stem cells in a mouse model of hindlimb ischemia, Regenerative Medicine, 10.2217/rme.13.17, 8:3, (283-293), Online publication date: 1-May-2013. Bai Y, Yin G, Huang Z, Liao X, Chen X, Yao Y and Pu X (2013) Localized delivery of growth factors for angiogenesis and bone formation in tissue engineering, International Immunopharmacology, 10.1016/j.intimp.2013.04.001, 16:2, (214-223), Online publication date: 1-Jun-2013. Lee T (2012) Bone marrow mesenchymal progenitor and stem cell biology and therapy Progenitor and Stem Cell Technologies and Therapies, 10.1533/9780857096074.3.345, (345-390), . Zhao D, Wang S, Feng Y, Hua C, Zhao J and Tang X (2011) Intratumoral c-Met expression is associated with vascular endothelial growth factor C expression, lymphangiogenesis, and lymph node metastasis in oral squamous cell carcinoma: implications for use as a prognostic marker, Human Pathology, 10.1016/j.humpath.2010.03.012, 42:10, (1514-1523), Online publication date: 1-Oct-2011. Lindsay C (2010) Novel therapeutic strategies for acute lung injury induced by lung damaging agents: The potential role of growth factors as treatment options, Human & Experimental Toxicology, 10.1177/0960327110376982, 30:7, (701-724), Online publication date: 1-Jul-2011. Kelsen S, Hall J and Chade A (2011) Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease, American Journal of Physiology-Renal Physiology, 10.1152/ajprenal.00089.2011, 301:1, (F218-F225), Online publication date: 1-Jul-2011. Saif J, Schwarz T, Chau D, Henstock J, Sami P, Leicht S, Hermann P, Alcala S, Mulero F, Shakesheff K, Heeschen C and Aicher A (2010) Combination of Injectable Multiple Growth Factor–Releasing Scaffolds and Cell Therapy as an Advanced Modality to Enhance Tissue Neovascularization, Arteriosclerosis, Thrombosis, and Vascular Biology, 30:10, (1897-1904), Online publication date: 1-Oct-2010. Li Y, Liang M, Yang Y, Hou X, Kong J, Xu J and Wang L (2010) Impact of acute pulmonary embolism on plasma and tissue hepatocyte growth factor: an experimental study, Experimental Lung Research, 10.3109/01902140903370055, 36:4, (237-242), Online publication date: 1-Apr-2010. Cimpean A, Seclaman E, Ceauşu R, Gaje P, Feflea S, Anghel A, Raica M and Ribatti D (2009) VEGF-A/HGF induce Prox-1 expression in the chick embryo chorioallantoic membrane lymphatic vasculature, Clinical and Experimental Medicine, 10.1007/s10238-009-0085-6, 10:3, (169-172), Online publication date: 1-Sep-2010. Hu W, Criswell M, Fong S, Temm C, Rajashekhar G, Cornell T and Clauss M (2009) Differences in the temporal expression of regulatory growth factors during choroidal neovascular development, Experimental Eye Research, 10.1016/j.exer.2008.10.014, 88:1, (79-91), Online publication date: 1-Jan-2009. Chen M, Hsieh C, Shih J, Chou C, Ma G, Chen T, Lee T, Tsai H, Cameron A and Chen C (2007) Proinflammatory macrophage migratory inhibition factor and interleukin-6 are concentrated in pleural effusion of human fetuses with prenatal chylothorax, Prenatal Diagnosis, 10.1002/pd.1704, 27:5, (435-441), Online publication date: 1-May-2007. Zhang G and Suggs L (2007) Matrices and scaffolds for drug delivery in vascular tissue engineering, Advanced Drug Delivery Reviews, 10.1016/j.addr.2007.03.018, 59:4-5, (360-373), Online publication date: 1-May-2007. Liu Y, Wilkinson F, Kirton J, Jeziorska M, Iizasa H, Sai Y, Nakashima E, Heagerty A, Canfield A and Alexander M (2007) Hepatocyte growth factor and c-Met expression in pericytes: implications for atherosclerotic plaque development, The Journal of Pathology, 10.1002/path.2155, 212:1, (12-19), Online publication date: 1-May-2007. Anghel A, Mut-Vitcu B, Savu L, Marian C, Seclaman E, Iman R, Neghina A and Dragulescu S (2007) Clinical improvement after treatment with VEGF165 in patients with severe chronic lower limb ischaemia, Genomic Medicine, 10.1007/s11568-007-9006-5, 1:1-2, (47-55), Online publication date: 1-Sep-2007. Pannitteri G, Petrucci E and Testa U (2006) Coordinate release of angiogenic growth factors after acute myocardial infarction: evidence of a two-wave production, Journal of Cardiovascular Medicine, 10.2459/01.JCM.0000253831.61974.b9, 7:12, (872-879), Online publication date: 1-Dec-2006. Fraser J, Wulur I, Alfonso Z and Hedrick M (2006) Fat tissue: an underappreciated source of stem cells for biotechnology, Trends in Biotechnology, 10.1016/j.tibtech.2006.01.010, 24:4, (150-154), Online publication date: 1-Apr-2006. Anitua E, Sanchez M, Nurden A, Zalduendo M, de la Fuente M, Orive G, Azofra J and Andia I (2006) Autologous fibrin matrices: A potential source of biological mediators that modulate tendon cell activities, Journal of Biomedical Materials Research Part A, 10.1002/jbm.a.30585, 77A:2, (285-293), Online publication date: 1-May-2006. Chade A (2013) Renal Vascular Structure and Rarefaction Comprehensive Physiology, 10.1002/cphy.c120012, (817-831) Nugrahaningrum D, Marcelina O, Liu C, Wu S and Kasim V (2020) Dapagliflozin Promotes Neovascularization by Improving Paracrine Function of Skeletal Muscle Cells in Diabetic Hindlimb Ischemia Mice Through PHD2/HIF-1α Axis, Frontiers in Pharmacology, 10.3389/fphar.2020.01104, 11 Makarevich P, Tsokolaeva Z, Shevelev A, Rybalkin I, Shevchenko E, Beloglazova I, Vlasik T, Tkachuk V, Parfyonova Y and Madeddu P (2012) Combined Transfer of Human VEGF165 and HGF Genes Renders Potent Angiogenic Effect in Ischemic Skeletal Muscle, PLoS ONE, 10.1371/journal.pone.0038776, 7:6, (e38776) Makarevich P, Dergilev K, Tsokolaeva Z, Boldyreva M, Shevchenko E, Gluhanyuk E, Gallinger J, Menshikov M, Parfyonova Y and Limana F (2018) Angiogenic and pleiotropic effects of VEGF165 and HGF combined gene therapy in a rat model of myocardial infarction, PLOS ONE, 10.1371/journal.pone.0197566, 13:5, (e0197566) February 18, 2005Vol 96, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000157575.66295.e0PMID: 15718506 Originally publishedFebruary 18, 2005 KeywordsVEGFantiinflammatoryHGFtherapeutic angiogenesisinflammationleukocytesPDF download Advertisement
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