Growth Factor Regulation of Physiologic Angiogenesis in the Mammary Gland

  • Anne Saaristo
  • Marika J. Karkkainen
  • Kari Alitalo
  • Roberto Montesano
  • M. Luisa Iruela-Arispe
  • Michael S. Pepper
Part of the Cardiovascular Molecular Morphogenesis book series (CARDMM)


During embryogenesis, the formation of new blood vessels occurs via two processes: vasculogenesis and angiogenesis. Vasculogenesis involves the de novo differentation of endothelial cells from mesoderm-derived precursors called angioblasts, which then cluster and reorganize to form capillary-like tubes (Risau and Flamme, 1995). Once the primary vascular plexus is formed, new capillaries form by sprouting or by splitting (intussusception) from preexisting capillaries in the processes called sprouting or nonsprouting angiogenesis, respectively (Risau, 1997). In postnatal life, the growth of normal as well as neoplastic tissues depends on angiogenesis. Angiogenesis is particularly important for normal reproductive function, including the cyclical growth of capillaries within the ovary (required for ovulation and corpus luteum formation) and the endometrium (required for regeneration following menstruation). Angiogenesis also occurs following implantation of the blastocyst, and is required for the formation of the placenta (Findlay, 1986). This chapter discusses the role of physiologic angiogenesis and angiogenic growth factors in relation to mammary gland function.


Vascular Endothelial Growth Factor Mammary Gland Hepatocyte Growth Factor Lymphatic Vessel Vascular Endothelial Growth Factor mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Achen, M. G., Jeltsch, M., Kukk, E., Makinen, T., Vitali, A., Wilks, A. F., Alitalo, K., and Stacker, S. A. 1998. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flkl) and VEGF receptor 3 (F1k4). Proc. Natl. Acad. Sci. USA. 95:548–553.PubMedCrossRefGoogle Scholar
  2. Alon, T., Hemo, I., Itin, A., Pe’er, J., Stone, J., and Keshet, E. 1995. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat. Med. 1:1024–1028.PubMedCrossRefGoogle Scholar
  3. Aprelikova, O., Pajusola, K., Partanen, J., Armstrong, E., Alitalo, R., Bailey, S. K., McMahon, J., Wasmuth, J., Huebner, K., and Alitalo, K. 1992. FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter. Cancer Res. 52:746–748.PubMedGoogle Scholar
  4. Bellomo, D., Headrick, J. P., Silins, G. U., Paterson, C. A., Thomas, P. S., Gartside, M., Mould, A., Cahill, M. M., Tonks, I. D., Grimmond, S. M., Townson, S., Wells, C., Little, M., Cummings, M. C., Hayward, N. K., and Kay, G. F. 2000. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86:E29–E35.PubMedCrossRefGoogle Scholar
  5. Benjamin, L. E., and Keshet, E. 1997. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc. Natl. Acad. Sci. USA 94:8761–8766.PubMedCrossRefGoogle Scholar
  6. Brown, L. F., Berse, B., Jackman, R. W., Tognazzi, K., Guidi, A. J., Dvorak, H. F., Senger, D. R., Connolly, J. L., and Schnitt, S. J. 1995. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum. Pathol. 26:86–91.PubMedCrossRefGoogle Scholar
  7. Carmeliet, P., Ferreira, V., Breier, G., Pollefeyt, S., Kieckens, L., Gertsenstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Ebenhardt, C., Declercq, C., Pawling, J., Moons, L., Collen, D., Risau, W., and Nagy, A. 1996. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439.PubMedCrossRefGoogle Scholar
  8. Daniel, C. W., and Silberstein, G. B. 1987. Postnatal development of rodent mammary gland. In: Neville, M. C., and Daniel, C. W., eds. The Mammary Gland. Plenum Press, New York, pp. 3–36.Google Scholar
  9. De Vries, C., Escobedo, J. A., Ueno, H., Houck, K., Ferrara, N., and Williams, L. T. 1992. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991.PubMedCrossRefGoogle Scholar
  10. Dumont, D. J., Gradwohl, G., Fong, G.-H., Puri, M. C., Gertsenstein, M., Auerbach, A., and Breitman, M. L. 1994. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dep. 8:1897–1909.CrossRefGoogle Scholar
  11. Dumont, D. J., Jussila, L., Taipale, J., Lymboussaki, A., Mustonen, T., Pajusola, K., Breitman, M., and Alitalo, K. 1998. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–949.PubMedCrossRefGoogle Scholar
  12. Dvorak, H. F., Brown, L. F., Detmar, M., and Dvorak, A. M. 1995. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146: 1029–1039.PubMedGoogle Scholar
  13. Feng, D., Nagy, J. A., Pyne, K., Hammel, I., Dvorak, H. F., and Dvorak, A. M. 1999. Pathways of macromolecular extravasation across microvascular endothelium in responce to VPF/VEGF and other vasoactive mediators. Microcirculation 6: 23–44.PubMedGoogle Scholar
  14. Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O’Shea, K. S., Powell-Braxton, L., Hilan, K. J., and Moore, M. W. 1996. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 438–442.CrossRefGoogle Scholar
  15. Ferrara, N., and Henzel, W. J. 1989. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161: 851–855.PubMedCrossRefGoogle Scholar
  16. Findlay, J. K. 1986. Angiogenesis in reproductive tissues. J. Endocrinol. 111:357–366. Galland, F., Karamysheva, A., Mattei, M.-G., Rosnet, O., Marchetto, S., and Birnbaum, D. 1992. Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene. Genomics 13: 475–478.Google Scholar
  17. Gasparini, G., Toi, M., Gion, M., Verderio, P., Dittadi, R., Hanatani, M., Matsubara, I., Vinante, O., Bonoldi, E., Boracchi, P., Gatti, C., Suzuki, H., and Tominaga, T. 1997. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J. Natl. Cancer Inst. 89: 139–147.PubMedCrossRefGoogle Scholar
  18. Gluzman-Poltorak, Z., Cohen, T., Herzog, Y., and Neufeld, G. 2000. Neuropilin-2 and neuropilin-1 are receptors for the 165-amino acid form of vascular endothelial growth factor (VEGF) and of placenta growth factor-2, but only neuropilin-2 functions as a receptor for the 145-amino acid form of VEGF. J. Biol. Chem. 275:18040–18045.PubMedCrossRefGoogle Scholar
  19. Greb, R. R., Maier, I., Wallwiener, D., and Kiesel, L. 1999. Vascular endothelial growth factor A (VEGF-A) mRNA expression levels decrease after menopause in normal breast tissue but not in breast cancer lesions. Br. J. Cancer. 81:225–231.PubMedCrossRefGoogle Scholar
  20. Haagensen, D. C. 1986. Diseases of the Breast, 3rd ed. W. B. Saunders, Philadelphia. Hauser, S., and Weich, H. A. 1993. A heparin-binding form of placenta growth factorGoogle Scholar
  21. (P1GF-2) is expressed in human umbilical vein endothelial cells and in placenta. Growth Google Scholar
  22. Factors 9:259–268.Google Scholar
  23. Hlatky, L., Tsionou, C., Hahnfeldt, P., and Coleman, C. N. 1994. Mammary fibroblasts may influence breast tumor angiogenesis via hypoksia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 54:6083–6086.PubMedGoogle Scholar
  24. Jeltsch, M., Kaipainen, A., Joukov, V., Meng, X., Lakso, M., Rauvala, H., Swartz, M., Fukumura, D., Jain, R. K., and Alitalo, K. 1997. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425.PubMedCrossRefGoogle Scholar
  25. Joukov, V., Pajusola, K., Kaipainen, A., Chilov, D., Lahtinen, I., Kukk, E., Saksela, O., Kalkkinen, N., and Alitalo, K. 1996. A novel vascular endothelial growth factor, VEGFC, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 15:290–298.PubMedGoogle Scholar
  26. Joukov, V., Sorsa, T., Kumar, V., Jeltsch, M., Claesson-Welsh, L., Cao, Y., Saksela, O., Kalkkinen, N., and Alitalo, K. 1997. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 16:3898–3911.PubMedCrossRefGoogle Scholar
  27. Kaipainen, A., Korhonen, J., Mustonen, T., van Hinsbergh, V. M., Fang, G.-H., Dumont, D., Breitman, M., and Alitalo, K. 1995. Expression of the fins-like tyrosine kinase FLT4 38 A. Saaristo et al gene becomes restricted to endothelium of lymphatic vessels during development. Proc. Natl. Acad. Sci. USA 92:3566–3570.PubMedCrossRefGoogle Scholar
  28. Karkkainen M., Valtola, R., Korpelainen E., and Alitalo, K. 1999. VEGF, VEGF-C and their receptors in tumor angigenesis and metastasis. In: Fidler, I. J., Niitsu, Y., Seiki, M., Sugimura, T., and Yokota, J., eds. Extended abstracts of the 29`h International Symposium of The Princess Takamatsu Cancer Research Fund. Molecular basis for invasion and metastasis. (Tokyo: Princess Takamatsu Cancer Research Fund), pp. 94–104.Google Scholar
  29. Kendall, R. L., and Thomas, K. A. 1993. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl. Acad. Sci. USA 90:10705–10709.PubMedCrossRefGoogle Scholar
  30. Lee, J., Gray, A., Yuan, J., Louth, S.-M., Avraham, H., and Wood, W. 1996. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc. Natl. Acad. Sci. USA 93:1988–1992.PubMedCrossRefGoogle Scholar
  31. Lichtenbeld, H. C., Barendsz-Janson, A. F., van Essen, H., Struijker, B., Griffioen, A. W., and Hillen, H. F. 1998. Angiogenic potential of malignant and non-malignant human breast tissues in an in vivo angiogenesis model. Int. J. Cancer 77:455–459.PubMedCrossRefGoogle Scholar
  32. Maglione, D., Guerriero, V., Viglietto, G., Delli-Bovi, P., and Persico, M. G. 1991. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Natl. Acad. Sci. USA 88:9267–9271.PubMedCrossRefGoogle Scholar
  33. Maisonpierre, P. C., Suri, C., Jones, P. F., Bartunkova, S., Wiegand, S. J., Radziejewski, C., Compton, D., McClain, J., Aldrich, T. H., Papadopoulos, N., Daly, T. J., Davis, S., Sato, T. N., and Yancopoulos, G. D. 1997. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60.PubMedCrossRefGoogle Scholar
  34. Makinen, T., Olofsson, B., Karpanen, T., Hellman, U., Soker, S., Klagsbrun, M., Eriksson, U., and Alitalo, K. 1999. Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J. Biol. Chem. 274:21217–21222.PubMedCrossRefGoogle Scholar
  35. Matsumoto, K., and Nakamura, T. 1996. Emerging multipotential aspects of hepatocyte growth factor. J. Biochem. 119:591–600.PubMedCrossRefGoogle Scholar
  36. Matsumoto, M., Kurohmaru, M., Hayashi, Y., Nishinakagawa, H., and Otsuka, J. 1994. Permeability of mammary gland capillaries to ferritin in mice. J. Vet. Med. Sci. 56:65–70.PubMedCrossRefGoogle Scholar
  37. Matsumoto, M., Nishinakagawa, H., Kurohmaru, M., Hayashi, Y., and Otsuka, J. 1992. Pregnancy and lactation affect the microvasculature of the mammary gland in mice. J. Vet. Med. Sci. 54:937–943.PubMedCrossRefGoogle Scholar
  38. Meyer, M., Clauss, M., Lepple-Wienhues, A., Waltenberger, J., Augustin, H. G., Ziche, M., Lanz, C., Böttner, M., Rziha, H.-J., and Dehio, C. 1999. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signaling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J. 18:363–374.PubMedCrossRefGoogle Scholar
  39. Migdal, M., Huppertz, B., Tessler, S., Comforti, A., Shibuya, M., Reich, R., Baumann, H., and Neufeld, G. 1998. Neuropilin-1 is a placenta growth factor-2 receptor./ Biol. Chem. 273:22272–22278.CrossRefGoogle Scholar
  40. Nakamura, J., Lu, Q., Aberdeen, G., Albrecht, E., and Brodie, A. 1999. The effect of estrogen on aromatase and vascular endothelial growth factor messenger ribonucleic acid in the normal nonhuman primate mammary gland. J. Clin. Endocrinol. Metab. 84:1432–1437.PubMedCrossRefGoogle Scholar
  41. Neufeld, G., Cohen, T., Gengrinovitch S., and Poltorak, Z. 1999. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13:9–22.PubMedGoogle Scholar
  42. Obermair, A., Kucera, E., Mayerhofer, K., Speicer, P., Seifert, M., Czerwenka, K., Kaider, A., Leodolter, S., Kainz, C., and Zellinger, R. 1997. Vascular endothelial growth factor (VEGF) in human breast cancer: correlation with disease-free survival. Int. J. Cancer. 74:455–458.PubMedCrossRefGoogle Scholar
  43. Ogawa, S., Oku, A., Sawano, A., Yamaguchi, S., Yazaki, Y., and Shibuya, M. 1998. A novel type of vascular endothelial growth factor: VEGF-E (NZ-7 VEGF) preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J. Biol. Chem. 273:31273–31282.PubMedCrossRefGoogle Scholar
  44. Olofsson, B., Korpelainen, E., Pepper, M. S., Mandriota, S. J., Aase, K., Kumar, V., Gunji, Y., Jeltsch, M. M., Shibuya, M., Alitalo, K., and Eriksson, U. 1998. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc. Natl. Acad. Sci. USA 95:11709–11714.PubMedCrossRefGoogle Scholar
  45. Olofsson, B., Pajusola, K., Kaipainen, A., Von Euler, G., Joukov, V., Saksela, O., Orpana, A., Pettersson, R. F., Alitalo, K., and Eriksson, U. 1996a. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc. Natl. Acad. Sci. USA 93:2576–2581.CrossRefGoogle Scholar
  46. Olofsson, B., Pajusola, K., von Euler, G., Chilov, D., Alitalo, K., and Eriksson, U. 1996b. Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J. Biol. Chem. 271:19310–19317.CrossRefGoogle Scholar
  47. Orlandini, M., Marconcini, L., Ferruzzi, R., and Oliviero, S. 1996. Identification of a c-fosinduced gene that is related to the platelet-derived growth factor/vascular endothelial growth factor family. Proc. Natl. Acad. Sci. USA 93:11675–11680.PubMedCrossRefGoogle Scholar
  48. Pajusola, K., Aprelikova, O., Armstrong, E., Morris, S., and Alitalo, K. 1993. Two human FLT4 receptor tyrosine kinase isoforms with distinct carboxyterminal tails are produced by alternative processing of primary transcripts. Oncogene 8:2931–2937.PubMedGoogle Scholar
  49. Partanen, J., Armstrong, E., Mäkelä, T. P., Korhonen, J., Sandberg, M., Renkonen, R., Knuutila, S., Huebner, K., and Alitalo, K. 1992. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol. Cell. Biol. 12:1698–1707.PubMedGoogle Scholar
  50. Partanen, T., Arola, J., Saaristo, A., Jussila, L., Ora, A., Miettinen, M., and Alitalo, K. 2000. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR3 in fenestrated blood vessels in human tissues. FASEB J. 14:2087–2096.PubMedCrossRefGoogle Scholar
  51. Pepper, M. S., Baetens, D., Mandriota, S., Di Sanza, C., Oikesmus, S., Lane, T. F., Soriano, J. V., Montesano, R., and Iruela-Arispe, L. 2000. Regulation of VEGF and VEGF receptor expression in the mammary gland during pregnancy, lactation and involution. Dey. Dyn. 218:507–524.CrossRefGoogle Scholar
  52. Pepper, M. S., Soriano, J. V. Menould, P.-A., Sappino A.-P., Orci, L., Montesano, R. 1995. Modulation of hepatocyte growth factor and c-met expression in the rat mammary gland during pregnancy, lactation and involution. Exp. Cell Res. 219:204–210.PubMedCrossRefGoogle Scholar
  53. Plouet, J., Schilling, J., and Gospodarowicz, D. 1989. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J. 8:3801–3806.PubMedGoogle Scholar
  54. Puri, M. C., Rossant, J., Alitalo, K., Bernstein, A., and Partanen, J. 1995. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J. 14:5884–5891.PubMedGoogle Scholar
  55. Risau, W. 1997. Mechanisms of angiogenesis. Nature 386:671–674.PubMedCrossRefGoogle Scholar
  56. Risau, W., and Flamme, I. 1995. Vasculogenesis. Annu. Rev. Cell Dep. Biol. 11:73–91.CrossRefGoogle Scholar
  57. Saaristo, A., Partanen, T. A., Jussila, L., Arola, J., Hytonen, M., Makitie, A., Vento, S., Kaipainen, A., Malmberg, H., and Alitalo, K. 2000. Vascular endothelial growth factor-C and its receptor VEGFR-3 in nasal mucosa and in nasopharyngeal tumors. Am. J. Pathol. 157:7–14.PubMedCrossRefGoogle Scholar
  58. Seetharam, L., Gotoh, N., Maru, Y., Neufeld, G., Yamaguchi, S., and Shibuya, M. 1995. A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 10:135–147.PubMedGoogle Scholar
  59. Shibuya, M., Yamaguchi, S., Yamane, A., Ikeda, T., Tojo, A., Matsushime, H., and Sato, M. 1990. Nucleotide sequence and expression of a novel human receptor type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5:519–524.PubMedGoogle Scholar
  60. Siafakas, C. G., Anatolitou, F., Fusunyan, R. D., Walker, W. A., and Sanderson, I. R. 1999. Vascular endothelial growth factor (VEGF) is present in human breast milk and its receptor is present on intestinal epithelial cells. Pediatr. Res. 45:652–657.PubMedCrossRefGoogle Scholar
  61. Soemarwoto, I. N., and Bern, H. A. 1958. The effects of hormones on the vascular pattern of the mouse mammary gland. Am. J. Anat. 103:403–435.PubMedCrossRefGoogle Scholar
  62. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G., and Klagsbrun, M. 1998. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745.PubMedCrossRefGoogle Scholar
  63. Soriano, J. V., Pepper, M. S., Nakamura, T., Orci, L., and Montesano, R. 1995. Hepatocyte growth factor stimulates extensive development of branching dut-like structures by cloned mammary gland epithelial cells. J. Cell. Sci. 108:413–430.PubMedGoogle Scholar
  64. Stirling, J. W., and Chandler, J. A. 1976. The fine structure of the normal, resting terminal ductal-lobular unit of the female breast. Virchows. Arch. [A] 372:205–226.CrossRefGoogle Scholar
  65. Suri, C., Jones, P. F., Patan, S., Bartunkova, S., Maisonpierre, P. C., Davis, S., Sato, T. N., and Yancopoulos, G. D. 1997. Requisite role of Angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1161–1169.Google Scholar
  66. Takahashi, A., Sasaki, H., Kim, S. J., Tobisu, K., Kakizoe, T., Tsukamoto, T., Kumamoto, Y., Sugimura, T., and Terada, M. 1994. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 54:4233–4237.PubMedGoogle Scholar
  67. Terman, B. I., Dougher-Vermazen, M., Carrion, M. E., Dimitrov, D., Armellino, D. C., Gospodarowicz, D., and Böhlen, P. 1992. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem. Biophys. Res. Commun. 187:1579–1586.PubMedCrossRefGoogle Scholar
  68. Thurston, G., Suri, C., Smith, K., McClain, J., Sato, T. N., Yancopoulos, G. D., and McDonald, D. M. 1999. Leakage-resistant blood vessels in mice transgenically over-expressing angiopoietin-1. Science 286:2511–2514.PubMedCrossRefGoogle Scholar
  69. Turner, C. W., and Gomez, E. T. 1933. The normal development of the mammary gland in the male and female albino mouse. Res. Bull. Mo. Agric. Exper. Sta. 182:3–43.Google Scholar
  70. Valtola, R., Salven, P., Heikkilä, P., Taipale, J., Joensuu, H., Rehn, M., Pihlajaniemi, T., Weich, H., de Waal, R., and Alitalo, K. 1999. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am. J. Pathol. 154:1381–1390.PubMedCrossRefGoogle Scholar
  71. Wahl, H. M. 1915. Development of the blood vessels of the mammary gland in the rabbit. Am. J. Anat. 18:515–524.CrossRefGoogle Scholar
  72. Waltenberger, J., Claesson-Welsh, L., Siegbahn, A., Shibuya, M., and Heldin, C.-H. 1994. Different signal transduction properties of KDR and Fltl, two receptors for vascular endothelial growth factor. J. Biol. Chem. 269:26988–26995.PubMedGoogle Scholar
  73. Weidner, N., Semple, J. P., Welch, W. R., and Folkman, J. 1991. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N. Engl. J. Med. 324:1–8.PubMedCrossRefGoogle Scholar
  74. Wise, L. M., Veikkola, T., Mercer, A. A., Savory, L. J., Fleming, S. B., Caesar, C., Vitali, A., Makinen, T., Alitalo, K., and Stacker, S. A. 1999. Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1. Proc. Natl. Acad. Sci. USA 96:3071–3076.PubMedCrossRefGoogle Scholar
  75. Yamada, Y., Nezu, J., Shimane, M., and Hirata, Y. 1997. Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics 42:483–488.PubMedCrossRefGoogle Scholar
  76. Yang, Y., Spitzer, E., Meyer, D., Sachs, M., Niemann, C., Hartmann, G., Weidner, K. M., Birchmeier, C., and Birchmeier, W. 1995. Sequential requirement of hepatocyte growth factor and neuregulin in morphogenesis and differentiation of the mammary gland. J. Cell. Biol. 131:215–226.PubMedCrossRefGoogle Scholar
  77. Yasugi, T., Kaido, T., and Uehara, Y. 1989. Changes in density and architecture of micro-vessels of the rat mammary gland during pregnancy and lactation. Arch. Histol. Cytol. 52:115–122.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Anne Saaristo
  • Marika J. Karkkainen
  • Kari Alitalo
  • Roberto Montesano
  • M. Luisa Iruela-Arispe
  • Michael S. Pepper

There are no affiliations available

Personalised recommendations