Cell and Tissue Research

, Volume 314, Issue 1, pp 5–14 | Cite as

VEGF and PlGF: two pleiotropic growth factors with distinct roles in development and homeostasis

  • Marc Tjwa
  • Aernout Luttun
  • Monica Autiero
  • Peter Carmeliet
Review

Abstract.

Blood vessels are crucial for normal development and growth by providing oxygen and nutrients. As shown by genetic targeting studies in mice, zebrafish and Xenopus blood vessel formation (or angiogenesis) is a multistep process, which is highly dependent on angiogenic growth factors such as VEGF, the founding member of the VEGF family. VEGF binds to the tyrosine kinase receptors VEGFR-1 and VEGFR-2, and loss of VEGF or its receptors results in abnormal angiogenesis and lethality during development. In contrast, PlGF, another member of this family, binds only to VEGFR-1, and appears to be crucial exclusively for pathological angiogenesis in the adult. However, the expression of VEGFR-1 and VEGFR-2 on non-vascular cells suggests additional biological properties for these growth factors. Indeed, the VEGF family and its receptors determine development and homeostasis of many organs, including the respiratory, skeletal, hematopoietic, nervous, renal and reproductive system, independent of their vascular role. These new insights broaden the activity spectrum of these "angiogenic" growth factors, and may have therapeutic implications when using these growth factors for vascular and/or non-vascular purposes.

Keywords

Vascular endothelial growth factor Placental growth factor VEGF receptors Signal transduction tyrosine kinase Angiogenesis Non-vascular targets 

References

  1. Agrawal R, et al. (2002) Concentration of vascular endothelial growth factor released by cultured human luteinized granulosa cells is higher in women with polycystic ovaries than in women with normal ovaries. Fertil Steril 78:1164–1169CrossRefPubMedGoogle Scholar
  2. Autiero M, et al. (2003) Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936–943Google Scholar
  3. Bagnard D, et al. (2001) Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J Neurosci 21:3332–3341PubMedGoogle Scholar
  4. Bergwerff M, et al. (1999) Unique vascular morphology of the fourth aortic arches: possible implications for pathogenesis of type-B aortic arch interruption and anomalous right subclavian artery. Cardiovasc Res 44:185–196Google Scholar
  5. Bhatt AJ, et al. (2001) Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med 164:1971–1980PubMedGoogle Scholar
  6. Brown LF, et al. (1995) Vascular permeability factor (vascular endothelial growth factor) is strongly expressed in the normal male genital tract and is present in substantial quantities in semen. J Urol 154:576–579PubMedGoogle Scholar
  7. Brusselmans K, et al. (2001) Hypoxia-inducible factor-2alpha (HIF-2alpha) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J Biol Chem 276:39192–39196PubMedGoogle Scholar
  8. Cao Y, et al. (1997) Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun 235:493–498CrossRefPubMedGoogle Scholar
  9. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395PubMedGoogle Scholar
  10. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660Google Scholar
  11. Carmeliet P, et al. (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439PubMedGoogle Scholar
  12. Carmeliet P, et al. (1999) Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med 5:495–502CrossRefPubMedGoogle Scholar
  13. Carmeliet P, et al. (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583CrossRefPubMedGoogle Scholar
  14. Charnock-Jones DS, et al. (1994) Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol Reprod 51:524–530PubMedGoogle Scholar
  15. Claesson-Welsh L (2003) Signal transduction by vascular endothelial growth factor receptors. Biochem Soc Trans 31:20–24PubMedGoogle Scholar
  16. Cleaver O, Krieg PA (1998) VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. Development 125:3905–3914PubMedGoogle Scholar
  17. Compernolle V, et al. (2002) Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8:702–710PubMedGoogle Scholar
  18. de Vries C, et al. (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991PubMedGoogle Scholar
  19. DiPalma T, et al. (1996) The placenta growth factor gene of the mouse. Mamm Genome 7:6–12Google Scholar
  20. Dorrell MI, Aguilar E, Friedlander M (2002) Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Invest Ophthalmol Vis Sci 43:3500–3510PubMedGoogle Scholar
  21. Duchek P, et al. (2001) Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 107:17–26Google Scholar
  22. Ema M, et al. (2003) Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse. Genes Dev 17:380–393CrossRefPubMedGoogle Scholar
  23. Eremina V, et al. (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111:707–716CrossRefPubMedGoogle Scholar
  24. Ferrara N, et al. (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442Google Scholar
  25. Ferrara N, et al. (1998) Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med 4:336–340PubMedGoogle Scholar
  26. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676Google Scholar
  27. Fong GH, et al. (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70PubMedGoogle Scholar
  28. Gerber HP, et al. (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5:623–628PubMedGoogle Scholar
  29. Gerber HP, et al. (2002) VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417:954–958CrossRefPubMedGoogle Scholar
  30. Gille H, et al. (2001) Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 276:3222–3230CrossRefPubMedGoogle Scholar
  31. Green CJ, et al. (2001) Placenta growth factor gene expression is induced by hypoxia in fibroblasts: a central role for metal transcription factor-1. Cancer Res 61:2696–2703PubMedGoogle Scholar
  32. Hackney JA, et al. (2002) A molecular profile of a hematopoietic stem cell niche. Proc Natl Acad Sci U S A 99:13061–13066CrossRefPubMedGoogle Scholar
  33. Haigh JJ, et al. (2000) Conditional inactivation of VEGF-A in areas of collagen2a1 expression results in embryonic lethality in the heterozygous state. Development 127:1445–1453PubMedGoogle Scholar
  34. Haruta H, Nagata Y, Todokoro K (2001) Role of Flk-1 in mouse hematopoietic stem cells. FEBS Lett 507:45–48CrossRefPubMedGoogle Scholar
  35. Hattori K, et al. (2001) Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med 193:1005–1014CrossRefPubMedGoogle Scholar
  36. Hattori K, et al. (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8:841–849PubMedGoogle Scholar
  37. Hauser S, Weich HA (1993) A heparin-binding form of placenta growth factor (PlGF-2) is expressed in human umbilical vein endothelial cells and in placenta. Growth Factors 9:259–268PubMedGoogle Scholar
  38. Hellstrom M, et al. (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055PubMedGoogle Scholar
  39. Hiratsuka S, et al. (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A 95:9349–9354CrossRefPubMedGoogle Scholar
  40. Houck KA, et al. (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267:26031–26037PubMedGoogle Scholar
  41. Iyer S, et al. (2001) The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 A resolution. J Biol Chem 276:12153–12161Google Scholar
  42. Jin K, et al. (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A 99:11946–11950CrossRefPubMedGoogle Scholar
  43. Kendall RL, Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A 90:10705–10709PubMedGoogle Scholar
  44. Kliche S, Waltenberger J (2001) VEGF receptor signaling and endothelial function. IUBMB Life 52:61–66CrossRefPubMedGoogle Scholar
  45. Korpelainen EI, et al. (1998) Overexpression of VEGF in testis and epididymis causes infertility in transgenic mice: evidence for nonendothelial targets for VEGF. J Cell Biol 143:1705–1712CrossRefPubMedGoogle Scholar
  46. Lambrechts D, et al. (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans, and protects motor neurons against ischemic death. Nat Genet 34:383–394Google Scholar
  47. LeCouter J, et al. (2001) Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412:877–884PubMedGoogle Scholar
  48. Leung DW, et al. (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309PubMedGoogle Scholar
  49. Li WE, et al. (2002) An essential role for connexin43 gap junctions in mouse coronary artery development. Development 129:2031–2042PubMedGoogle Scholar
  50. Liao EC, et al. (1998) SCL/Tal-1 transcription factor acts downstream of cloche to specify hematopoietic and vascular progenitors in zebrafish. Genes Dev 12:621–626PubMedGoogle Scholar
  51. Lindsay EA (2001) Chromosomal microdeletions: dissecting del22q11 syndrome. Nat Rev Genet 2:858–868CrossRefPubMedGoogle Scholar
  52. Luo H, et al. (2002) Vascular endothelial growth factor (VEGF) promotes the early development of bovine embryo in the presence of cumulus cells. J Vet Med Sci 64:967–971CrossRefPubMedGoogle Scholar
  53. Luttun A, Carmeliet P (2003) Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? J Clin Invest 111:600–602CrossRefPubMedGoogle Scholar
  54. Luttun A, et al. (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840PubMedGoogle Scholar
  55. Maes C, et al. (2002) Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev 111:61–73CrossRefPubMedGoogle Scholar
  56. Maglione D, et al. (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 88:9267–9271PubMedGoogle Scholar
  57. Maglione D, et al. (1993) Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene 8:925–931Google Scholar
  58. Mattot V, et al. (2002) Loss of the VEGF(164) and VEGF(188) isoforms impairs postnatal glomerular angiogenesis and renal arteriogenesis in mice. J Am Soc Nephrol 13:1548–1560PubMedGoogle Scholar
  59. Maynard SE, et al. (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658CrossRefPubMedGoogle Scholar
  60. McDonald NQ, Hendrickson WA (1993) A structural superfamily of growth factors containing a cystine knot motif. Cell 73:421–424PubMedGoogle Scholar
  61. Migdal M, et al. (1998) Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 273:22272–22278CrossRefPubMedGoogle Scholar
  62. Muller YA, et al. (1997) The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 Å resolution: multiple copy flexibility and receptor binding. Structure 5:1325–1338PubMedGoogle Scholar
  63. Nakajima Y, et al. (1997) Expression of smooth muscle alpha-actin in mesenchymal cells during formation of avian endocardial cushion tissue: a role for transforming growth factor beta3. Dev Dyn 209:296–309CrossRefPubMedGoogle Scholar
  64. Nalbandian A, et al. (2003) Expression of vascular endothelial growth factor receptors during male germ cell differentiation in the mouse. Biol Reprod 69:985–994Google Scholar
  65. Nasevicius A, Larson J, Ekker SC (2000) Distinct requirements for zebrafish angiogenesis revealed by a VEGF-A morphant. Yeast 17:294–301CrossRefPubMedGoogle Scholar
  66. Neufeld G, et al. (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22PubMedGoogle Scholar
  67. Obermair A, et al. (1999) Vascular endothelial growth factor and its receptors in male fertility. Fertil Steril 72:269–275CrossRefPubMedGoogle Scholar
  68. Ohwada A, et al. (2003) VEGF regulates the proliferation of acid-exposed alveolar lining epithelial cells. Thorax 58:328–332CrossRefPubMedGoogle Scholar
  69. Oosthuyse B, et al. (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131–138PubMedGoogle Scholar
  70. Othman-Hassan K, et al. (2001) Arterial identity of endothelial cells is controlled by local cues. Dev Biol 237:398–409PubMedGoogle Scholar
  71. Pardanaud L, et al. (1996) Two distinct endothelial lineages in ontogeny, one of them related to hemopoiesis. Development 122:1363–1371Google Scholar
  72. Park JE, et al. (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269:25646–25654PubMedGoogle Scholar
  73. Perelman N, et al. (2003) Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood 102:1506–1514Google Scholar
  74. Persico MG, Vincenti V, DiPalma T (1999) Structure, expression and receptor-binding properties of placental growth factor (PlGF). Curr Top Microbiol Immunol 237:31–40PubMedGoogle Scholar
  75. Poole TJ, Finkelstein EB, Cox CM (2001) The role of FGF and VEGF in angioblast induction and migration during vascular development. Dev Dyn 220:1–17CrossRefPubMedGoogle Scholar
  76. Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684CrossRefPubMedGoogle Scholar
  77. Robert B, Zhao X, Abrahamson DR (2000) Coexpression of neuropilin-1, Flk1, and VEGF(164) in developing and mature mouse kidney glomeruli. Am J Physiol Renal Physiol 279:F275–282PubMedGoogle Scholar
  78. Roman BL, Weinstein BM (2000) Building the vertebrate vasculature: research is going swimmingly. Bioessays 22:882–893CrossRefPubMedGoogle Scholar
  79. Sadler TW (2000) Cardiovascular system. Langman's Medical Embryology. Williams & Wilkins, Baltimore, pp 208–259Google Scholar
  80. Sawano A, et al. (2001) Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97:785–791CrossRefPubMedGoogle Scholar
  81. Senger DR, et al. (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985PubMedGoogle Scholar
  82. Shalaby F, et al. (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66PubMedGoogle Scholar
  83. Shibuya M (2001) Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Struct Funct 26:25–35PubMedGoogle Scholar
  84. Sondell M, Sundler F, Kanje M (2000) Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci 12:4243–4254CrossRefPubMedGoogle Scholar
  85. Stalmans I, et al. (2002) Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109:327–336CrossRefPubMedGoogle Scholar
  86. Stalmans I, et al. (2003) VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nat Med 9:173–182CrossRefPubMedGoogle Scholar
  87. Street J, et al. (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A 99:9656–9661CrossRefPubMedGoogle Scholar
  88. Sun Y, et al. (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:1843–1851CrossRefPubMedGoogle Scholar
  89. Tordjman R, et al. (2001) Erythroblasts are a source of angiogenic factors. Blood 97:1968–1974CrossRefPubMedGoogle Scholar
  90. Torry DS, et al. (1996) Vascular endothelial growth factor expression in cycling human endometrium. Fertil Steril 66:72–80PubMedGoogle Scholar
  91. Visvader JE, Fujiwara Y, Orkin SH (1998) Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development. Genes Dev 12:473–479PubMedGoogle Scholar
  92. Vitelli F, et al. (2002) Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Hum Mol Genet 11:915–922CrossRefPubMedGoogle Scholar
  93. Wiesmann C, et al. (1997) Crystal structure at 1.7 Å resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91 695–704Google Scholar
  94. Yamashita J, et al. (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408:92–96CrossRefPubMedGoogle Scholar
  95. Yancopoulos GD, et al. (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248PubMedGoogle Scholar
  96. Zelzer E, et al. (2002) Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129:1893–1904PubMedGoogle Scholar
  97. Zerlin M, Goldman JE (1997) Interactions between glial progenitors and blood vessels during early postnatal corticogenesis: blood vessel contact represents an early stage of astrocyte differentiation. J Comp Neurol 387:537–546CrossRefPubMedGoogle Scholar
  98. Zhu J, et al. (2002) beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 129:2891–2903PubMedGoogle Scholar
  99. Zhu Y, et al. (2003) Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J 17:186–193CrossRefPubMedGoogle Scholar
  100. Ziegler BL, et al. (1999) KDR receptor: a key marker defining hematopoietic stem cells. Science 285:1553–1558CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Marc Tjwa
    • 1
  • Aernout Luttun
    • 1
  • Monica Autiero
    • 1
  • Peter Carmeliet
    • 1
    • 2
  1. 1.The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for BiotechnologyUniversity of LeuvenLeuvenBelgium
  2. 2.The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for BiotechnologyKU LeuvenLeuvenBelgium

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