Cancer and Metastasis Reviews

, Volume 26, Issue 2, pp 281–290 | Cite as

Hypoxia: A key regulator of angiogenesis in cancer



Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases resulting in hypoxia. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and metabolites. The key regulator of hypoxia-induced angiogenesis is the transcription factor hypoxia inducible factor (HIF)-1. Multiple HIF-1 target genes have been shown to modulate angiogenesis by promoting the mitogenic and migratory activities of endothelial cells. Because of this, hypoxia-induced angiogenesis has become an attractive target for cancer therapy, however the mechanisms involved during this process and how best to target it for cancer therapy are still under investigation. This review will cover the current understanding of hypoxia-induced tumor angiogenesis and discuss the caveats of hypoxia-targeted antiangiogenic therapy for the treatment of cancer.


Hypoxia Angiogenesis Cancer HIF 


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  1. 1.
    Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. New England Journal of Medicine, 285, 1182–1186.PubMedCrossRefGoogle Scholar
  2. 2.
    Gimbrone, M. A., Jr., Leapman, S. B., Cotran, R. S., & Folkman, J. (1972). Tumor dormancy in vivo by prevention of neovascularization. Journal of Experimental Medicine, 136, 261–276.PubMedCrossRefGoogle Scholar
  3. 3.
    Brem, S., Brem, H., Folkman, J., Finkelstein, D., & Patz, A. (1976). Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Research, 36, 2807–2812.PubMedGoogle Scholar
  4. 4.
    Parangi, S., O’Reilly, M., Christofori, G., Holmgren, L., Grosfeld, J., Folkman, J. et al. (1996). Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 93, 2002–2007.PubMedCrossRefGoogle Scholar
  5. 5.
    Holmgren, L., O’Reilly, M. S., Folkman, J. (1995). Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Medicine, 1, 149–153.CrossRefGoogle Scholar
  6. 6.
    Carmeliet, P. (2000). Mechanisms of angiogenesis and arteriogenesis. Nature Medicine, 6, 389–395.CrossRefGoogle Scholar
  7. 7.
    Bergers, G., & Benjamin, L. E. (2003). Tumorigenesis and the angiogenic switch. Nature Reviews Cancer, 3, 401–410.PubMedCrossRefGoogle Scholar
  8. 8.
    Naumov, G. N., Akslen, L. A., & Folkman, J. (2006). Role of angiogenesis in human tumor dormancy: Animal models of the angiogenic switch. Cell Cycle, 5, 1779–1787.PubMedGoogle Scholar
  9. 9.
    Folkman, J., Watson, K., Ingber, D., & Hanahan, D. (1989). Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature, 339, 58–61.PubMedCrossRefGoogle Scholar
  10. 10.
    North, S., Moenner, M., & Bikfalvi, A. (2005). Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors. Cancer Letter, 218, 1–14.CrossRefGoogle Scholar
  11. 11.
    Lin. E. Y., Li, J. F., Gnatovskiy, L., Deng, Y., Zhu, L., Grzesik, D. A., et al. (2006). Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Research, 66, 11238–11246.PubMedCrossRefGoogle Scholar
  12. 12.
    Nozawa, H., Chiu, C., & Hanahan, D. (2006). Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 103, 12493–12498.PubMedCrossRefGoogle Scholar
  13. 13.
    Holash, J., Maisonpierre, P. C., Compton. D., Boland, P., Alexander, C. R., Zagzag, D., et al. (1999). Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science, 284, 1994–1998.PubMedCrossRefGoogle Scholar
  14. 14.
    Giordano, F. J., & Johnson, R. S (2001). Angiogenesis: The role of the microenvironment in flipping the switch. Current Opinion in Genetics & Development, 11, 35–40.CrossRefGoogle Scholar
  15. 15.
    Semenza, G. L. (2004). Hydroxylation of HIF-1: Oxygen sensing at the molecular level. Physiology (Bethesda), 19, 176–182.Google Scholar
  16. 16.
    Peng, J., Zhang, L., Drysdale, L., & Fong, G. H. (2000). The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proceedings of the National Academy of Sciences of the United States of America, 97, 8386–8391.PubMedCrossRefGoogle Scholar
  17. 17.
    Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y., & Fujii-Kuriyama, Y. (1997). A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proceedings of the National Academy of Sciences of the United States of America, 94, 4273–4278.PubMedCrossRefGoogle Scholar
  18. 18.
    Makino, Y., Cao, R., Svensson, K., Bertilsson, G., Asman, M., Tanaka, H., et al. (2001). Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature, 414, 550–554.PubMedCrossRefGoogle Scholar
  19. 19.
    Ryan, H. E., Lo, J., & Johnson, R. S. (1998). HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO Journal, 17, 3005–3015.PubMedCrossRefGoogle Scholar
  20. 20.
    Maxwell, P. H., Dachs, G. U., Gleadle, J. M., Nicholls, L. G., Harris, A. L., Stratford, I. J., et al. (1997). Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 94, 8104–8109.PubMedCrossRefGoogle Scholar
  21. 21.
    Stoeltzing, O., McCarty, M. F., Wey, J. S., Fan, F., Liu, W., Belcheva, A., et al. (2004) Ellis LM: Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth, angiogenesis, and vessel maturation. Journal of the National Cancer Institute, 96, 946–956.PubMedCrossRefGoogle Scholar
  22. 22.
    Jensen, R. L., Ragel, B. T., Whang, K., & Gillespie, D. (2006). Inhibition of hypoxia inducible factor-1alpha (HIF-1alpha) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas. Journal of Neuro-oncology, 78, 233–247.PubMedCrossRefGoogle Scholar
  23. 23.
    Bos, R., Zhong, H., Hanrahan, C. F., Mommers, E. C., Semenza, G. L., Pinedo, H. M., et al. (2001) Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. Journal of the National Cancer Institute, 93, 309–314PubMedCrossRefGoogle Scholar
  24. 24.
    Liao, D., Corle, C., Seagroves, T. N., & Johnson, R. S. (2007). Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Research, 67, 563–572.PubMedCrossRefGoogle Scholar
  25. 25.
    Tang, N., Wang, L., Esko, J., Giordano, F. J., Huang, Y., Gerber, H. P., et al. (2004). Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell, 6, 485–495.PubMedCrossRefGoogle Scholar
  26. 26.
    Kondo, K., & Kaelin, W. G., Jr. (2001) The von Hippel-Lindau tumor suppressor gene. Experimental Cell Research, 264, 117–125.PubMedCrossRefGoogle Scholar
  27. 27.
    Mahon, P. C., Hirota, K., & Semenza, G. L. (2001). FIH-1: A novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes & Development, 15, 2675–2686.CrossRefGoogle Scholar
  28. 28.
    Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (1996). FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes & Development, 16, 1466–1471.CrossRefGoogle Scholar
  29. 29.
    Arany, Z., Huang, L. E., Eckner, R., Bhattacharya, S., Jiang, C., Goldberg, M. A., et al. (1996). An essential role for p300/CBP in the cellular response to hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 93, 12969–12973.PubMedCrossRefGoogle Scholar
  30. 30.
    Richard, D. E., Berra, E., Gothie, E., Roux, D., & Pouyssegur, J. (1999). p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. Journal of Biological Chemistry, 274, 32631–32637.PubMedCrossRefGoogle Scholar
  31. 31.
    Mylonis, I., Chachami, G., Samiotaki, M., Panayotou, G., Paraskeva, E., Kalousi, A., et al. (2006). Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha. Journal of Biological Chemistry, 281, 33095–33106.PubMedCrossRefGoogle Scholar
  32. 32.
    Shaw, R. J., & Cantley, L. C. (2006). Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature, 441, 424–430.PubMedCrossRefGoogle Scholar
  33. 33.
    Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M. M., et al. (2000) Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Research, 60, 1541–1545.PubMedGoogle Scholar
  34. 34.
    Blancher, C., Moore, J. W., Robertson, N., & Harris, A. L. (2001) Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3′-kinase/Akt signaling pathway. Cancer Research, 61, 7349–7355.PubMedGoogle Scholar
  35. 35.
    Poulaki, V., Mitsiades, C. S., McMullan, C., Sykoutri, D., Fanourakis, G., Kotoula, V., et al. (2003). Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism, 88, 5392–5398.PubMedCrossRefGoogle Scholar
  36. 36.
    Zundel, W., Schindler, C., Haas-Kogan, D., Koong, A., Kaper, F., Chen, E., et al. (2000). Loss of PTEN facilitates HIF-1-mediated gene expression. Genes & Development, 14, 391–396.Google Scholar
  37. 37.
    Grunstein, J., Masbad, J. J., Hickey, R., Giordano, F., & Johnson, R. S. (2000) Isoforms of vascular endothelial growth factor act in a coordinate fashion To recruit and expand tumor vasculature. Molecular and Cellular Biology, 20, 7282–7291.PubMedCrossRefGoogle Scholar
  38. 38.
    Forsythe, J. A., Jiang, B. H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., et al. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Molecular and Cellular Biology, 16, 4604–4613.PubMedGoogle Scholar
  39. 39.
    Olsson, A. K., Dimberg, A., Kreuger, J., & Claesson-Welsh, L. (2006). VEGF receptor signalling—in control of vascular function. Nature Reviews Molecular Cell Biology, 7, 359–371.PubMedCrossRefGoogle Scholar
  40. 40.
    Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O’Shea, K. S., et al. (1996). Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature, 380, 439–442.PubMedCrossRefGoogle Scholar
  41. 41.
    Grunstein, J., Roberts, W. G., Mathieu-Costello, O., Hanahan, D., Johnson, R. S. (1999). Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Research, 59, 1592–1598.PubMedGoogle Scholar
  42. 42.
    Mancuso, M. R., Davis, R., Norberg, S. M., O’Brien, S., Sennino, B., Nakahara, T. et al. (2006). Rapid vascular regrowth in tumors after reversal of VEGF inhibition. Journal of Clinical Investigation, 116, 2610–2621.PubMedCrossRefGoogle Scholar
  43. 43.
    Das, B., Yeger, H., Tsuchida, R., Torkin, R., Gee, M. F., Thorner, P. S. et al. (2005). A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Research, 65, 7267–7275.PubMedCrossRefGoogle Scholar
  44. 44.
    Morbidelli, L., Donnini, S., & Ziche, M. (2003). Role of nitric oxide in the modulation of angiogenesis. Current Pharmaceutical Design, 9, 521–530.PubMedCrossRefGoogle Scholar
  45. 45.
    Kimura, H., Weisz, A., Kurashima, Y., Hashimoto, K., Ogura, T., D’Acquisto, F., et al. (2000). Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: Control of hypoxia-inducible factor-1 activity by nitric oxide. Blood, 95, 189–197.PubMedGoogle Scholar
  46. 46.
    Palmer, L. A., Semenza, G. L., Stoler, M. H., & Johns, R. A. (1998). Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. American Journal of Physiology, 274, L212–219.PubMedGoogle Scholar
  47. 47.
    Jung, F., Palmer, L. A., Zhou, N., & Johns, R. A. (2000). Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes. Circulation Research, 86, 319–325.PubMedGoogle Scholar
  48. 48.
    Coulet, F., Nadaud, S., Agrapart, M., & Soubrier, F. (2003). Identification of hypoxia-response element in the human endothelial nitric oxide synthase gene promoter. Journal of Biological Chemistry, 278, 46230–46240.PubMedCrossRefGoogle Scholar
  49. 49.
    Cooke, J. P. (2003). NO and angiogenesis. Atherosclerosis. Supplement, 4, 53–60.CrossRefGoogle Scholar
  50. 50.
    Rossig, L., Fichtlscherer, B., Breitschopf, K., Haendeler, J., Zeiher, A. M., Mulsch, A., et al. (1999). Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. Journal of Biological Chemistry, 274, 6823–6826.PubMedCrossRefGoogle Scholar
  51. 51.
    Ellies, L. G, Fishman, M., Hardison, J., Kleeman, J., Maglione, J. E., Manner, C. K. et al. (2003). Mammary tumor latency is increased in mice lacking the inducible nitric oxide synthase. International Journal of Cancer, 106, 1–7.CrossRefGoogle Scholar
  52. 52.
    Cullis, E. R., Kalber, T. L., Ashton, S. E., Cartwright, J. E., Griffiths, J. R., Ryan, A. J., et al. (2006). Tumour overexpression of inducible nitric oxide synthase (iNOS) increases angiogenesis and may modulate the anti-tumour effects of the vascular disrupting agent ZD6126. Microvascular Research, 71, 76–84.PubMedCrossRefGoogle Scholar
  53. 53.
    Grose, R., & Dickson, C. (2005). Fibroblast growth factor signaling in tumorigenesis. Cytokine & Growth Factor Reviews, 16, 179–186.CrossRefGoogle Scholar
  54. 54.
    Shi, Y. H., Wang, Y. X., Bingle, L., Gong, L. H., Heng, W. J., Li, Y., et al. (2005). In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways. Journal of Pathology, 205, 530–536.PubMedCrossRefGoogle Scholar
  55. 55.
    Pore, N., Liu, S., Haas-Kogan, D. A., O’Rourke, D. M., & Maity, A. (2003). PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Research, 63, 236–241.PubMedGoogle Scholar
  56. 56.
    Calvani, M., Rapisarda, A., Uranchimeg, B., Shoemaker. R. H., & Melillo, G. (2006). Hypoxic induction of an HIF-1alpha-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells. Blood, 107, 2705–2712.PubMedCrossRefGoogle Scholar
  57. 57.
    Li, J., Shworak, N. W., & Simons, M. (2002). Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites. Journal of Cell Science, 115, 1951–1959.PubMedGoogle Scholar
  58. 58.
    Brat, D. J., & Mapstone, T. B. (2003). Malignant glioma physiology: Cellular response to hypoxia and its role in tumor progression. Annals of Internal Medicine, 138, 659–668.PubMedGoogle Scholar
  59. 59.
    Arteaga, C. L. (2002). Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist, 7(Suppl 4), 31–39.PubMedCrossRefGoogle Scholar
  60. 60.
    Ueda, S., Basaki, Y., Yoshie, M., Ogawa, K., Sakisaka, S., Kuwano, M., et al. (2006). PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib. Cancer Research, 66, 5346–5353.PubMedCrossRefGoogle Scholar
  61. 61.
    Amin, D. N., Hida, K., Bielenberg, D. R., & Klagsbrun, M. (2006). Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Research, 66, 2173–2180.PubMedCrossRefGoogle Scholar
  62. 62.
    Yoshida, D., Kim, K., Noha, M., & Teramoto, A. (2006). Hypoxia inducible factor 1-alpha regulates of platelet derived growth factor-B in human glioblastoma cells. Journal of Neuro-oncology, 76, 13–21.PubMedCrossRefGoogle Scholar
  63. 63.
    Nakamura, K., Taguchi, E., Miura, T., Yamamoto, A., Takahashi, K., Bichat, F., et al. (2006). KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Research, 66, 9134–9142.PubMedCrossRefGoogle Scholar
  64. 64.
    Lederle, W., Stark, H. J., Skobe, M., Fusenig, N. E., & Mueller, M. M. (2006). Platelet-derived growth factor-BB controls epithelial tumor phenotype by differential growth factor regulation in stromal cells. American Journal of Pathology, 169, 1767–1783.PubMedCrossRefGoogle Scholar
  65. 65.
    Pages, G., & Pouyssegur, J. (2005). Transcriptional regulation of the Vascular Endothelial Growth Factor gene–a concert of activating factors. Cardiovascular Research, 65, 564–573.PubMedCrossRefGoogle Scholar
  66. 66.
    Huang, S., Pettaway, C. A., Uehara, H., Bucana, C. D., & Fidler, I. J. (2001). Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene, 20, 4188–4197.PubMedCrossRefGoogle Scholar
  67. 67.
    Schmidt, D., Textor, B., Pein, O. T., Licht, A. H., Andrecht, S., Sator-Schmitt, et al. (2007). Critical role for NF-kappaB-induced JunB in VEGF regulation and tumor angiogenesis. EMBO Journal, 26, 710–719.PubMedCrossRefGoogle Scholar
  68. 68.
    Mizukami, Y., Li, J., Zhang, X., Zimmer, M. A., Iliopoulos, O., & Chung, D. C. (2004). Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Research, 64, 1765–1772.PubMedCrossRefGoogle Scholar
  69. 69.
    Mizukami, Y., Jo, W. S., Duerr, E. M., Gala, M., Li, J., Zhang, X., et al. (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nature Medicine, 11, 992–997.Google Scholar
  70. 70.
    Semenza, G. L. (2003). Targeting HIF-1 for cancer therapy. Nature Reviews Cancer, 3, 721–732.PubMedCrossRefGoogle Scholar
  71. 71.
    Fukumura, D., Xavier, R., Sugiura, T., Chen, Y., Park, E. C., Lu N., Selig, M., et al. (1998). Tumor induction of VEGF promoter activity in stromal cells. Cell, 94, 715–725.PubMedCrossRefGoogle Scholar
  72. 72.
    Blouw, B., Song, H., Tihan, T., Bosze, J., Ferrara, N., Gerber, H. P., et al. (2003). The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell, 4, 133–146.PubMedCrossRefGoogle Scholar
  73. 73.
    Zaman, K., Ryu, H., Hall, D., O’Donovan, K., Lin, K. I., Miller M. P., et al. (1999). Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. Journal of Neuroscience, 19, 9821–9830.PubMedGoogle Scholar
  74. 74.
    Siddiq, A., Ayoub, I. A., Chavez, J. C., Aminova, L., Shah, S., LaManna, J. C., et al. (2005). Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. Journal of Biological Chemistry, 280, 41732–41743.PubMedCrossRefGoogle Scholar
  75. 75.
    Lee, H. J., Kim, K. S., Park, I. H., & Kim, S. U. (2007). Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS ONE 2: e156.Google Scholar
  76. 76.
    Oosthuyse, B., Moons, L., Storkebaum, E., Beck, H., Nuyens, D., Brusselmans, K., et al. (2001). Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genetics, 28, 131–138PubMedCrossRefGoogle Scholar
  77. 77.
    Martinez, P., Esbrit, P., Rodrigo, A., Alvarez-Arroyo, M. V., Martinez, M. E. (2002). Age-related changes in parathyroid hormone-related protein and vascular endothelial growth factor in human osteoblastic cells. Osteoporosis International, 13, 874–881.PubMedCrossRefGoogle Scholar
  78. 78.
    Thebaud, B., Ladha, F., Michelakis, E. D., Sawicka, M., Thurston, G., Eaton, F., et al. (2005). Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation, 112, 2477–2486.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Molecular PathologyUniversity of California San DiegoSan DiegoUSA
  2. 2.Department of BiologyUniversity of California San DiegoSan DiegoUSA

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