Abstract
The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell–cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.
Similar content being viewed by others
References
Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 377-386, 1980
Palmer RMJ, Ferrige AS, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327: 524-526, 1987
Knowles RG, Moncada S: Nitric oxide synthases in mammals. Biochem J 298: 249-258, 1994
Morris SM, Billiar TR: New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 266: E829-E839, 1994
Michel T, XieQW, Nathan C: Molecular biological analysis of nitric oxide synthases. In: Feelisch M, Stamler J (eds) Methods in Nitric oxide Research. John Wiley and Sons, NY, 1996, pp 161-175
Gnanapandithen K, Chen Z, Kau CL, Gorenzynski RM, Marsden PA: Cloning and characterization of murine endothelial constitutive nitric oxide synthase. Biochimica et Biophysica Acta 1308: 103-106, 1996
Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC: Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377: 239-242, 1995
Lee PC, Salyapongse AN, Bragdon GA, Shears LL 2nd, Watkins SC, Edington HD, Billiar TR: Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol 277: H1600-H1608, 1999
MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, Stevens K, Xie Q-W, Sokol K, Hutchinson N, Chen H, Mudgett JS: Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81: 641-650, 1995
Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC: Targeted disruption of the neuronal nitric oxide synthase gene. Cell 175: 1273-1286, 1993
Moncada S, Palmer RMJ, Higgs A: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109-142, 1991
Wink DA, Hanbauer I, Laval F, Cook JA, Krishna MC, Mitchell JB: Nitric oxide protects against the cytotoxic effects of reactive oxygen species. Ann NY Acad Sci 738: 265-278, 1994
Ziche M, Morbidelli L, Pacini M, Geppetti P, Alessandri G, Maggi CA: Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res 40: 264-278, 1990
Morbidelli L, Parenti A, Giovannelli L, Granger HJ, Ledda F, Ziche M: Bi receptor involvement in the effect of bradykinin on venular endothelial cell proliferation and potentiation of FGF-2 effects. Br J Pharmacol 124(6): 1286-1292, 1998
Pipili-Synetos B, Sakkoula B, Maragoudakis ME: Nitric oxide is involved in the regulation of angiogenesis. Br J Pharmacol 108: 855-857, 1993
Leibovicz JS, Polverini PJ, Fong TW, Harlow LA, Kock AE: Production of angiogenic activity by human monocytes requires an L-arginine/nitric oxide-synthasedependent effector mechanism. Proc Natl Acad Sci USA 91: 4190-4194, 1994
Montrucchio G, Lupia B, De Martino A, Battaglia B, Arese M, Tizzani A, Bussolino F, Camussi G: Nitric oxide mediates angiogenesis induced in vivo by platelet-activating factor and tumor necrosis factor. AmJ Pathol 151: 557-563, 1997
Brzozowski T, Kounturek SJ, Drozdowicz D, Dembinski A, Stachura J: Healing of chronic gastric ulcerations by L-arginine. Digestion 56: 463-471, 1995
Ziehe M, Morbidelli L, Masini B, Granger HJ, Geppetti G, Ledda F: Nitric oxide promotes DNA synthesis and cyclic GMP formation in endothelial cells from postcapillary venules. Biochem Biophys Res Commun 192(3): 1198-1203, 1993
Ziche M, Morbidelli L, Masini B, Amerini S, Granger HJ, Maggi CA, Geppetti P, Ledda F: Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 94: 2036-2044, 1994
Ziche M, Morbidelli L, Parenti A, Amerini S, Granger HJ, Maggi CA: Substance P increases cyclic GMP levels on coronary postcapillary venular endothelial cells. Life Sci 53: 1105-1112, 1993
Ziche M, Morbidelli L, Choudhuri R, Zhang H-T, Donnini S, Granger HJ, Bicknell R: Nitric oxide-synthase lies downstream of vascular endothelial growth factor but not basic fibroblast growth factor induced angiogenesis. J Clin Invest 99: 2625-2634, 1997
Ziche M, Parenti A, Ledda F, Dell'Era P, Granger HJ, Maggi CA, Presta M: Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Circ Res 80: 845-852, 1997
Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocrine Reviews 18: 4-25, 1997
Ku DD, Zaleski JK, Lin S, Brock TA: Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol 265: H586-H592, 1993
Wu HM, Qiaobing H, Yuan Y, Granger HJ: VEGF induces NO-dependent hyperpermeability in coronary venules. Am J Physiol 269(38): C1371-C1378, 1996
Morbidelli L, Chang C-H, Douglas JG, Granger HJ, Ledda F, Ziche M: Nitric oxide mediates the mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 270(39): H411-H415, 1996
Hood JD, Ziche M, Granger HG: VEGE upregulates ecNOS message, protein, and NO production. Am J Physiol 274: H1054-H1058, 1998
Hood J, Granger HJ: Protein kinase C mediates vascular endothelial growth factor-induced raf-1 activation and proliferation in human endothelial cells. J Biol Chem 273: 23504-23508, 1998
Parenti A, Morbidelli L, Cui XL, Douglas JG, Hood J, Granger HJ, Ledda F, Ziche M: Nitric oxide is an upstream signal for vascular endothelial growth factor-induced extracellular signal-regulated kinases 1/2 activation in postcapillary endothelium. J Biol Chem 273: 4220-4226, 1998
Salom JB, Orti M, Centeno JM, Torregrosa G, Alborch E: Reduction of infarct size by the NO donors sodium nitroprusside and spermine/NO after transient focal cerebral ischemia in rats. Brain Res 865: 149-156, 2000
Cobbs CS, Brenman JE, Alpade KD, Bredt DS, Israel MA: Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res 55: 727-730, 1995
Thomsen LL, Lawton FG, Knowles RG, Beesley JE, Riveros-Moreno V, Moncada S: Nitric oxide synthase activity in human gynecological cancer. Cancer Res 54: 1352-1354, 1994
Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S: Nitric oxide synthase activity in human breast cancer. Br J Cancer 72: 41-44, 1995
Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I, Vergari WA, Ziche M: Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst 90: 587-596, 1998
Klotz T, Bloch W, Jacobs G, Niggemann S, Englemann U, Addicks K: Immunolocalization of inducible and constitutive nitric oxide synthases in human bladder cancer. Urology 54: 416-419, 1999
Klotz T, Bloch W, Volberg C, Englemann U, Addicks K: Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer 82: 1897-1903, 1998
Thomsen LL, Miles DW: Role of nitric oxide in tumor progression: Lessons from human tumors. Cancer Metast Rev 17: 107-118, 1998
Thomsen LL, Scott JMJ, Topley P, Knowles RG, Keerie AJ, Frend AJ: Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo. Studies with 1400W, a novel inhibitor. Cancer Res 57: 3300-3304, 1997
Fukumura D, Jain RK: Role of nitric oxide in angiogenesis and microcirculation in tumors. Cancer Metast Rev 17: 77-89, 1998
Jenkins DC, Charles IG, Thomsen LL, Moss DW, Holmes LS, Baylis SA, Rhodes P, Westmore K, Emson PC, Moncada S: Role of nitric oxide in tumor angiogenesis. Proc Natl Acad Sci USA 92: 4392-4396, 1995
Ghigo D, Arese M, Todde R, Vecchi A, Silvagno F, Costamagna C, Dong QG, Alessio M, Heller R, Soldi R: Middle T antigen-transformed endothelial cells exhibit an increased activity of nitric oxide synthase. J Exp Med 181: 9-19, 1995
Orucevic A, Lala PK: NG-nitroL-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumor growth in adenocarcinoma-bearing mice. Br J Cancer 73: 189-196, 1996
Doi K, Akaike T, Horie H, Noguchi Y, Fuji S, Beppu T, OgawaM, Maeda H: Excessive production ofNO in rat solid tumor and its implication in rapid tumor growth. Cancer 77: 1598-1604, 1996
Wolff JEA, Guerin C, Laterra J, Bressler J, Indurti RR, Brem H, Goldstein GW: Dexamethasone reduces vascular density and plasminogen activator activity in 9L rat brain tumors. Brain Res 604: 79-85, 1993
Zhang H-T, Craft P, Scott PAE, Ziche M, Weich HA, Harris AL, Bicknell R: Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J Natl Cancer Inst 87: 213-217, 1995
Jadeski LC, Lala PK: Nitric oxide synthase inhibition by N(G)-intro-L-arginine methyl ester inhibits tumor induced angiogenesis in mammary tumors. Am J Pathol 155: 1381-1390, 1999
Orucevic A, Bechberger J, Green AM, Shapiro RA, Billiar TR, Lala PK: Nitric oxide production by mammary adenocarcinoma cells promotes tumor-cell invasiveness. Int J Cancer 81: 889-896, 1999
Stuher DJ, Nathan CF: Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med 169: 1543-1555, 1989
Albina JE, Reichner JS: Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis. Cancer Metast Rev 17: 39-53, 1998
Xie K, Huang S, Dong Z, Juang S-H, Gutman M, Xie Q-W, Nathan C, Fidler IJ: Transfection with inducible nitric oxide synthase gene suppresses tumorgenicity and abrogates metastasis in K-1735 murine melanoma cells. J Exp Med 181: 1333-1343, 1995
Xie K, Fidler IJ: Therapy of cancer metastasis by activation of the inducible nitric oxide synthase. Cancer Metast Rev 17: 55-75, 1998
Xie K, Huang S, Dong Z, Juang S-H, Wang Y, Fidler IJ: Destruction of bystander cells by tumor cells transfected with inducible nitric oxide (NO) synthase gene. J Natl Cancer Inst 89: 421-427, 1997
Ambs S, Hussain SP, Harris CC: Interactive effects of nitric oxide and the p53 tumor suppressor gene in carcinogenesis and tumor progression. FASEB J 11: 443-448, 1997
Ambs S, Merriam WG, Ogunfusika MO, Bennet WP, Ishibe N, Hussain SP, Tzeng FL, Geller DA, Billiar TR, Harris CC: p53 and vascular endothelial growth factor regulate tumor growth of NOS-2 expressing human carcinoma cells. Nat Medi 4: 1371-1376, 1998
Wink D, Kasprazak K, Maragos C, Elespuru R, Misra M, Dumus T, Cebula T, Koch W, Andrews A, Allan J, Keefer L: DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 254: 1001-1003, 1991
Nicotera P, Bernassola F, Melino G: Nitric oxide (NO), a signaling molecule with a killer soul. Cell Death Differ 6: 931-933, 1999
Beckman JS, Koppenol WH: Nitric oxide, superoxide and peroxynitrite: the good, the bad and the ugly. Am J Physiol 271: C1424-C1437, 1996
Ellie F, Loiseau H, Lafond F, Arsaut J, Demotes-Mainard J: Differential expression of inducible nitric oxide synthase in human brain tumors. Neuroreport 7: 294-296, 1995
Fujisawa H, Ogura T, Hokari A, Weisz A, Yamashita J, Esumi H: Inducible nitric oxide synthase in a human glioblastoma cell line. J Neurochem 64: 85-91, 1995
Hara E, Takahashi K, Tominaga T, Kumabe T, Kayama T, Suzuki H, Fujita H, Yoshimoto T, Shirato K, Shibahara S: Expression of heme oxygenase and inducible nitric oxide synthase mRNA in human brain tumors. Biochem Biophys Res Commun 224(l): 153-158, 1996
Bakshi A, Nag TC, Wadhwa S, Mahapatra AK, Sarkar C: The expression of nitric oxide in human brain tumors and peritumoral areas. J Neurol Sci 155(2): 196-203, 1998
Iwata S, Nakagawa K, Harada H, Oka Y, Kumon Y, Sakaki S: Endothelial nitric oxide synthase expression in tumor vasculature is correlated with malignancy in human supratentorial astrocytic tumors. Neurosurgery 45: 24-28, 1999
Munoz-Fernandez MA, Fresno M: Involvement of nitric oxide on the cytokine induced growth of glial cell. Biochem Biophys Res Commun 194: 319-325, 1993
Ferrante R, Kowall N, Beal ME, Richardson EP Jr, Bird ED, Martin JB: Selective sparing of a class of striatal neurons in Huntington's disease. Science(Washington DC) 230: 561-563, 1985
Stoll G, Jander S, Schroeter M: Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol 56: 149-171, 1998
Yuan F, Salehi HA, Boucher Y, Vasthare US, Tuma RE, Jain RK: Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res 54: 4564-4568, 1994
Tozer GM, Prise VE, Chaplin DJ: Inhibition of nitric oxide synthase induces a selective reduction in tumor blood flow that is reversible with L-arginine. Cancer Res 57: 948-955, 1997
Fukumura D, Yan F, Endo M, Jain RK: Role of nitric oxide in tumor microcirculation. Blood flow, vascular permeability, and leukocyte-endothelial interactions. Am J Pathol 150: 713-725, 1997
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ziche, M., Morbidelli, L. Nitric Oxide and Angiogenesis. J Neurooncol 50, 139–148 (2000). https://doi.org/10.1023/A:1006431309841
Issue Date:
DOI: https://doi.org/10.1023/A:1006431309841