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Molecular regulation of vessel maturation

Abstract

The maturation of nascent vasculature, formed by vasculogenesis or angiogenesis, requires recruitment of mural cells, generation of an extracellular matrix and specialization of the vessel wall for structural support and regulation of vessel function. In addition, the vascular network must be organized so that all the parenchymal cells receive adequate nutrients. All of these processes are orchestrated by physical forces as well as by a constellation of ligands and receptors whose spatio-temporal patterns of expression and concentration are tightly regulated. Inappropriate levels of these physical forces or molecules produce an abnormal vasculature—a hallmark of various pathologies. Normalization of the abnormal vasculature can facilitate drug delivery to tumors and formation of a mature vasculature can help realize the promise of therapeutic angiogenesis and tissue engineering.

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Figure 1: Wall composition of nascent versus mature vessels.

Debbie Maizels

Figure 2: Steps in network formation and maturation during embryonic (physiological) angiogenesis (a) and tumor (pathological) angiogenesis (b).

Debbie Maizels

Figure 3: Vessel normalization and EC–mural cell interactions in tumors growing in dorsal windows in mice.

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References

  1. Folkman, J. Angiogenesis. in Harrison's Principles of International Medicine (eds. Braunwald, E. et al.) 517–530 (McGraw-Hill, New York, 2001).

    Google Scholar 

  2. Jain, R.K. & Carmeliet, P.F. Vessels of death or life. Sci. Am. 285, 38–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nat. Med. 6, 389–395 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Yancopoulos, G.D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Carmeliet, P. & Jain, R.K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Nguyen, L.L. & D'Amore, P.A. Cellular interactions in vascular growth and differentiation. Int. Rev. Cytol. 204, 1–48 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Rossant, J. & Howard, L. Signaling pathways in vascular development. Annu. Rev. Cell Dev. Biol. 18, 541–573 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Ferrara, N. VEGF and the quest for tumour angiogenesis factors. Nat. Rev. Cancer 2, 795–803 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Nagy, J.A. et al. VEGF-A induces angiogenesis, arteriogenesis, lymphangiogenesis, and vascular malformations. Cold Spring Harbor Symposium on Quantitative Biology 67, 227–237 (2002).

    Google Scholar 

  10. Hellstrom, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kluk, M.J. & Hla, T. Signaling of sphingosine-1-phosphate via the S1P/EDG-family of G-protein-coupled receptors. Biochim. Biophys. Acta 1582, 72–80 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Kluk, M.J., Colmont, C., Wu, M.T. & Hla, T. Platelet-derived growth factor (PDGF)-induced chemotaxis does not require the G protein-coupled receptor S1P1 in murine embryonic fibroblasts and vascular smooth muscle cells. FEBS Lett. 533, 25–28 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Cho, H., Kozasa, T., Bondjers, C., Betsholtz, C. & Kehrl, J.H. Pericyte-specific expression of Rgs5: implications for PDGF and EDG receptor signaling during vascular maturation. FASEB J. 13, 440–442 (2003).

    Google Scholar 

  14. Loughna, S. & Sato, T.N. Angiopoietin and Tie signaling pathways in vascular development. Matrix Biol. 20, 319–325 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Uemura, A. et al. Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J. Clin. Invest. 110, 1619–1628 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pepper, M.S. Transforming growth factor-β: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 8, 21–43 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Chambers, R.C., Leoni, P., Kaminski, N., Laurent, G.J. & Heller, R.A. Global expression profiling of fibroblast responses to transforming growth factor-β(1) reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching. Am. J. Pathol. 162, 533–546 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gohongi, T. et al. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor β1. Nat. Med. 5, 1203–1208 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Weinstein, M., Yang, X. & Deng, C. Functions of mammalian Smad genes as revealed by targeted gene disruption in mice. Cytokine Growth Factor Rev. 11, 49–58 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Goumans, M.J. et al. Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J. 21, 1743–1753 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mukouyama, Y.S., Shin, D., Britsch, S., Taniguchi, M. & Anderson, D.J. Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 109, 693–705 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Neufeld, G. et al. The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc. Med. 12, 13–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Kalluri, R. Basement membranes: structural features, assembly, cellular interactions and role in cancer angiogenesis. Nat. Rev. Cancer (in the press).

  24. Lawler, J. The functions of thrombospondin-1 and-2. Curr. Opin. Cell Biol. 12, 634–640 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Hynes, R.O. A reevaluation of integrins as regulators of angiogenesis. Nat. Med. 8, 918–921 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Stupack, D.G. & Cheresh, D.A. Get a ligand, get a life: integrins, signaling and cell survival. J. Cell Sci. 115, 3729–3738 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Fukai, N. et al. Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J. 21, 1535–1544 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Drake, C.J., Cheresh, D.A. & Little, C.D. An antagonist of integrin αVβ3 prevents maturation of blood vessels during embryonic neovascularization. J. Cell Sci. 108, 2655–2661 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Ruoslahti, E. Specialization of tumour vasculature. Nat. Rev. Cancer 2, 83–90 (2002).

    Article  PubMed  Google Scholar 

  30. Alitalo, K. & Carmeliet, P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1, 219–227 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Wilting, J., Tomarev, S. & Christ, B. Lymphangioblasts in embryonic lymphangiogenesis. Lymphatic Res. Biol. 1, 33–44 (2003).

    Article  Google Scholar 

  32. Salven, P., Mustjoki, S., Alitalo, R., Alitalo, K. & Rafii, S. VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells. Blood 101, 168–172 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Jain, R.K. & Padera, T.P. Development. Lymphatics make the break. Science 299, 209–210 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Boardman, K.C. & Swartz, M.A. Interstitial flow as a guide for lymphangiogenesis. Circ. Res. 92, 801–808 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Topper, J.N. & Gimbrone, M.A., Jr. Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype. Mol. Med. Today 5, 40–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Semenza, G.L. HIF-1 and mechanisms of hypoxia sensing. Curr. Opin. Cell Biol. 13, 167–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Xu, L., Fukumura, D. & Jain, R.K. Acidic extracellular pH induces vascular endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2 MAPK signaling pathway: mechanism of low pH-induced VEGF. J. Biol. Chem. 277, 11368–11374 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Helisch, A. & Schaper, W. Arteriogenesis - the development and growth of collateral arteries. Microcirculation 10, 83–97 (2003).

    Article  PubMed  Google Scholar 

  39. Coussens, L.M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tomasek, J.J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R.A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Zawicki, D.F., Jain, R.K., Schmid-Schoenbein, G.W. & Chien, S. Dynamics of neovascularization in normal tissue. Microvasc. Res. 21, 27–47 (1981).

    Article  CAS  PubMed  Google Scholar 

  42. Bloch, W. et al. The angiogenesis inhibitor endostatin impairs blood vessel maturation during wound healing. FASEB J. 14, 2373–2376 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Altavilla, D. et al. Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse. Diabetes 50, 667–674 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Carmeliet, P. Angiogenesis in health and disease. Nat. Med. 9, 653–660 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Jain, R.K. Angiogenesis and lymphangiogenesis in tumors: insights from intravital microscopy. Cold Spring Harbor Symposium on Quantitative Biology 67, 239–248 (2002).

    Google Scholar 

  46. Jain, R.K., Munn, L.L. & Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2, 266–276 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Helmlinger, G., Yuan, F., Dellian, M. & Jain, R.K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat. Med. 3, 177–182 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Baish, J.W. & Jain, R.K. Fractals and cancer. Cancer Res. 60, 3683–3688 (2000).

    CAS  PubMed  Google Scholar 

  49. Helmlinger, G., Netti, P.A., Lichtenbeld, H.C., Melder, R.J. & Jain, R.K. Solid stress inhibits the growth of multicellular tumor spheroids. Nat. Biotechnol. 15, 778–783 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Chang, Y.S. et al. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc. Natl. Acad. Sci. USA 97, 14608–14613 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Melder, R.J. et al. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat. Med. 2, 992–997 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Morikawa, S. et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 160, 985–1000 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Brown, E.B. et al. In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nat. Med. 7, 864–868 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Hobbs, S.K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA 95, 4607–4612 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jain, R.K. & Munn, L.L. Leaky vessels? Call Ang1! Nat. Med. 6, 131–132 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Ramanujan, S., Koenig, G.C., Padera, T.P., Stoll, B.R. & Jain, R.K. Local imbalance of proangiogenic and antiangiogenic factors: a potential mechanism of focal necrosis and dormancy in tumors. Cancer Res. 60, 1442–1448 (2000).

    CAS  PubMed  Google Scholar 

  59. Jain, R.K. & Fenton, B.T. Intratumoral lymphatic vessels: a case of mistaken identity or malfunction? J. Natl. Cancer Inst. 94, 417–421 (2002).

    Article  PubMed  Google Scholar 

  60. Padera, T.P. et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883–1886 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Jain, R.K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Jain, R.K. et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc. Natl. Acad. Sci. USA 95, 10820–10825 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R.K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Kadambi, A. et al. Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-receptor 2 and host VEGF-A. Cancer Res. 61, 2404–2408 (2001).

    CAS  PubMed  Google Scholar 

  65. Benjamin, L.E., Golijanin, D., Itin, A., Pode, D. & Keshet, E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J. Clin. Invest. 103, 159–165 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Isner, J.M. Myocardial gene therapy. Nature 415, 234–239 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Langer, R. Where a pill won't reach. Sci. Am. 288, 50–57 (2003).

    Article  PubMed  Google Scholar 

  69. Baumgartner, I. et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 97, 1114–1123 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Dellian, M., Witwer, B.P., Salehi, H.A., Yuan, F. & Jain, R.K. Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment. Am. J. Pathol. 149, 59–71 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Richardson, T.P., Peters, M.C., Ennett, A.B. & Mooney, D.J. Polymeric system for dual growth factor delivery. Nat. Biotechnol. 19, 1029–1034 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Thurston, G. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat. Med. 6, 460–463 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Li, J. et al. PR39, a peptide regulator of angiogenesis. Nat. Med. 6, 49–55 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Linden, T. et al. The antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesis. FASEB J. 17, 761–763 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Vincent, K.A. et al. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1α/VP16 hybrid transcription factor. Circulation 102, 2255–2261 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Shyu, K.G. et al. Intramyocardial injection of naked DNA encoding HIF-1α/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc. Res. 54, 576–583 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Elson, D.A. et al. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α. Genes Dev. 15, 2520–2532 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schechner, J.S. et al. In vivo formation of complex microvessels lined by human endothelial cells in an immunodeficient mouse. Proc. Natl. Acad. Sci. USA 97, 9191–9196 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yang, J. et al. Telomerized human microvasculature is functional in vivo. Nat. Biotechnol. 19, 219–224 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Hirschi, K.K., Rohovsky, S.A., Beck, L.H., Smith, S.R. & D'Amore, P.A. Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Circ. Res. 84, 298–305 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Darland, D.C. & D'Amore, P.A. TGF β is required for the formation of capillary-like structures in three-dimensional cocultures of 10T1/2 and endothelial cells. Angiogenesis 4, 11–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Niklason, L.E. et al. Functional arteries grown in vitro. Science 284, 489–493 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Levenberg, S., Golub, J.S., Amit, M., Itskovitz-Eldor, J. & Langer, R. Endothelial cells derived from human embryonic stem cells. Proc. Natl. Acad. Sci. USA 99, 4391–4396 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yamashita, J. et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408, 92–96 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Yurugi-Kobayashi, T. et al. Effective contribution of transplanted vascular progenitor cells derived from embryonic stem cells to adult neovascularization in proper differentiation stage. Blood 101, 2675–2678 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Jiang, Y. et al. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp. Hematol. 30, 896–904 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Kocher, A.A. et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 7, 430–436 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Simper, D., Stalboerger, P.G., Panetta, C.J., Wang, S. & Caplice, N.M. Smooth muscle progenitor cells in human blood. Circulation 106, 1199–1204 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Majka, S.M. et al. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration. J. Clin. Invest. 111, 71–79 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 8, 831–840 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Rafii, S. et al. Contribution of marrow-derived progenitors to vascular and cardiac regeneration. Semin. Cell Dev. Biol. 13, 61–67 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Stoll, B.R., Migliorini, C., Kadambi, A., Munn, L.L. & Jain, R.K. A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in solid tumors: implications for anti-angiogenic therapy. Blood (in the press).

  93. Schmid-Schoenbein, G. The second valve system in lymphatics. Lymphatic Res. Biol. 1, 25–29 (2003).

    Article  Google Scholar 

  94. Reyes, M. et al. Origin of endothelial progenitors in human postnatal bone marrow. J. Clin. Invest. 109, 337–346 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hungerford, J.E. & Little, C.D. Developmental biology of the vascular smooth muscle cell: building a multilayered vessel wall. J. Vasc. Res. 36, 2–27 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Sartore, S. et al. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ. Res. 89, 1111–1121 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Elenbaas, B. & Weinberg, R.A. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp. Cell Res. 264, 169–184 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Powell, D.W. et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am. J. Physiol. 277, C1–C9 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. McDonald, D.M. & Choyke, P.L. Imaging of angiogenesis: from microscope to clinic. Nat. Med. 9, 713–725 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Gazit, Y. et al. Fractal characteristics of tumor vascular architecture during tumor growth and regression. Microcirculation 4, 395–402 (1997).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Due to length limitations, references cited are limited to review articles and Supplementary Table 1 online. The author apologizes to the authors of the original articles not cited. The author thanks R. Jones, P. D'Amore, D. McDonald, and J. Samson, and members of the Steele Lab, especially N. Koike, L. Munn, R. Tong, E. di Tomaso, D. Duda, Y. Boucher, J. Baish, D. Fukumura and B. Stoll, for their invaluable help in preparing this manuscript. The author's work is supported by grants from the National Cancer Institute.

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Jain, R. Molecular regulation of vessel maturation. Nat Med 9, 685–693 (2003). https://doi.org/10.1038/nm0603-685

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