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

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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.

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References

  • 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 78:1164–1169

    Article  PubMed  Google Scholar 

  • Autiero M, et al. (2003) Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936–943

    Google Scholar 

  • 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 21:3332–3341

    CAS  PubMed  Google Scholar 

  • 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 44:185–196

    Google Scholar 

  • 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 164:1971–1980

    CAS  PubMed  Google Scholar 

  • 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 154:576–579

    CAS  PubMed  Google Scholar 

  • 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 276:39192–39196

    CAS  PubMed  Google Scholar 

  • Cao Y, et al. (1997) Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun 235:493–498

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  • Carmeliet P, et al. (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    CAS  PubMed  Google Scholar 

  • 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 5:495–502

    Article  CAS  PubMed  Google Scholar 

  • 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 7:575–583

    Article  CAS  PubMed  Google Scholar 

  • Charnock-Jones DS, et al. (1994) Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol Reprod 51:524–530

    CAS  PubMed  Google Scholar 

  • Claesson-Welsh L (2003) Signal transduction by vascular endothelial growth factor receptors. Biochem Soc Trans 31:20–24

    PubMed  Google Scholar 

  • Cleaver O, Krieg PA (1998) VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. Development 125:3905–3914

    CAS  PubMed  Google Scholar 

  • 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 8:702–710

    CAS  PubMed  Google Scholar 

  • de Vries C, et al. (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991

    PubMed  Google Scholar 

  • DiPalma T, et al. (1996) The placenta growth factor gene of the mouse. Mamm Genome 7:6–12

    CAS  Google Scholar 

  • 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 43:3500–3510

    PubMed  Google Scholar 

  • Duchek P, et al. (2001) Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 107:17–26

    CAS  Google Scholar 

  • Ema M, et al. (2003) Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse. Genes Dev 17:380–393

    Article  CAS  PubMed  Google Scholar 

  • Eremina V, et al. (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111:707–716

    Article  CAS  PubMed  Google Scholar 

  • Ferrara N, et al. (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442

    Google Scholar 

  • Ferrara N, et al. (1998) Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med 4:336–340

    CAS  PubMed  Google Scholar 

  • Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    CAS  Google Scholar 

  • Fong GH, et al. (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70

    CAS  PubMed  Google Scholar 

  • Gerber HP, et al. (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5:623–628

    CAS  PubMed  Google Scholar 

  • Gerber HP, et al. (2002) VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417:954–958

    Article  CAS  PubMed  Google Scholar 

  • 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 276:3222–3230

    Article  CAS  PubMed  Google Scholar 

  • 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 61:2696–2703

    CAS  PubMed  Google Scholar 

  • Hackney JA, et al. (2002) A molecular profile of a hematopoietic stem cell niche. Proc Natl Acad Sci U S A 99:13061–13066

    Article  CAS  PubMed  Google Scholar 

  • Haigh JJ, et al. (2000) Conditional inactivation of VEGF-A in areas of collagen2a1 expression results in embryonic lethality in the heterozygous state. Development 127:1445–1453

    CAS  PubMed  Google Scholar 

  • Haruta H, Nagata Y, Todokoro K (2001) Role of Flk-1 in mouse hematopoietic stem cells. FEBS Lett 507:45–48

    Article  CAS  PubMed  Google Scholar 

  • 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 193:1005–1014

    Article  CAS  PubMed  Google Scholar 

  • Hattori K, et al. (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8:841–849

    CAS  PubMed  Google Scholar 

  • 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 9:259–268

    CAS  PubMed  Google Scholar 

  • 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 126:3047–3055

    CAS  PubMed  Google Scholar 

  • 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 95:9349–9354

    Article  CAS  PubMed  Google Scholar 

  • Houck KA, et al. (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267:26031–26037

    CAS  PubMed  Google Scholar 

  • 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 276:12153–12161

    CAS  Google Scholar 

  • Jin K, et al. (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A 99:11946–11950

    Article  CAS  PubMed  Google Scholar 

  • 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 90:10705–10709

    CAS  PubMed  Google Scholar 

  • Kliche S, Waltenberger J (2001) VEGF receptor signaling and endothelial function. IUBMB Life 52:61–66

    Article  CAS  PubMed  Google Scholar 

  • 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 143:1705–1712

    Article  CAS  PubMed  Google Scholar 

  • 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 34:383–394

    Google Scholar 

  • LeCouter J, et al. (2001) Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412:877–884

    CAS  PubMed  Google Scholar 

  • Leung DW, et al. (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    CAS  PubMed  Google Scholar 

  • Li WE, et al. (2002) An essential role for connexin43 gap junctions in mouse coronary artery development. Development 129:2031–2042

    CAS  PubMed  Google Scholar 

  • Liao EC, et al. (1998) SCL/Tal-1 transcription factor acts downstream of cloche to specify hematopoietic and vascular progenitors in zebrafish. Genes Dev 12:621–626

    CAS  PubMed  Google Scholar 

  • Lindsay EA (2001) Chromosomal microdeletions: dissecting del22q11 syndrome. Nat Rev Genet 2:858–868

    Article  CAS  PubMed  Google Scholar 

  • 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 64:967–971

    Article  CAS  PubMed  Google Scholar 

  • Luttun A, Carmeliet P (2003) Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? J Clin Invest 111:600–602

    Article  CAS  PubMed  Google Scholar 

  • 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 8:831–840

    CAS  PubMed  Google Scholar 

  • 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 111:61–73

    Article  CAS  PubMed  Google Scholar 

  • 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 88:9267–9271

    CAS  PubMed  Google Scholar 

  • 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 8:925–931

    CAS  Google Scholar 

  • 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 13:1548–1560

    CAS  PubMed  Google Scholar 

  • 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 111:649–658

    Article  CAS  PubMed  Google Scholar 

  • McDonald NQ, Hendrickson WA (1993) A structural superfamily of growth factors containing a cystine knot motif. Cell 73:421–424

    CAS  PubMed  Google Scholar 

  • Migdal M, et al. (1998) Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 273:22272–22278

    Article  CAS  PubMed  Google Scholar 

  • 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 5:1325–1338

    CAS  PubMed  Google Scholar 

  • 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 209:296–309

    Article  CAS  PubMed  Google Scholar 

  • Nalbandian A, et al. (2003) Expression of vascular endothelial growth factor receptors during male germ cell differentiation in the mouse. Biol Reprod 69:985–994

    Google Scholar 

  • Nasevicius A, Larson J, Ekker SC (2000) Distinct requirements for zebrafish angiogenesis revealed by a VEGF-A morphant. Yeast 17:294–301

    Article  CAS  PubMed  Google Scholar 

  • Neufeld G, et al. (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22

    CAS  PubMed  Google Scholar 

  • Obermair A, et al. (1999) Vascular endothelial growth factor and its receptors in male fertility. Fertil Steril 72:269–275

    Article  CAS  PubMed  Google Scholar 

  • Ohwada A, et al. (2003) VEGF regulates the proliferation of acid-exposed alveolar lining epithelial cells. Thorax 58:328–332

    Article  CAS  PubMed  Google Scholar 

  • Oosthuyse B, et al. (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131–138

    CAS  PubMed  Google Scholar 

  • Othman-Hassan K, et al. (2001) Arterial identity of endothelial cells is controlled by local cues. Dev Biol 237:398–409

    CAS  PubMed  Google Scholar 

  • Pardanaud L, et al. (1996) Two distinct endothelial lineages in ontogeny, one of them related to hemopoiesis. Development 122:1363–1371

    CAS  Google Scholar 

  • 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 269:25646–25654

    CAS  PubMed  Google Scholar 

  • Perelman N, et al. (2003) Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood 102:1506–1514

    Google Scholar 

  • Persico MG, Vincenti V, DiPalma T (1999) Structure, expression and receptor-binding properties of placental growth factor (PlGF). Curr Top Microbiol Immunol 237:31–40

    CAS  PubMed  Google Scholar 

  • Poole TJ, Finkelstein EB, Cox CM (2001) The role of FGF and VEGF in angioblast induction and migration during vascular development. Dev Dyn 220:1–17

    Article  CAS  PubMed  Google Scholar 

  • Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684

    Article  CAS  PubMed  Google Scholar 

  • 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:F275–282

    CAS  PubMed  Google Scholar 

  • Roman BL, Weinstein BM (2000) Building the vertebrate vasculature: research is going swimmingly. Bioessays 22:882–893

    Article  CAS  PubMed  Google Scholar 

  • Sadler TW (2000) Cardiovascular system. Langman's Medical Embryology. Williams & Wilkins, Baltimore, pp 208–259

  • 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 97:785–791

    Article  CAS  PubMed  Google Scholar 

  • Senger DR, et al. (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985

    CAS  PubMed  Google Scholar 

  • Shalaby F, et al. (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66

    PubMed  Google Scholar 

  • Shibuya M (2001) Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Struct Funct 26:25–35

    CAS  PubMed  Google Scholar 

  • 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 12:4243–4254

    Article  CAS  PubMed  Google Scholar 

  • Stalmans I, et al. (2002) Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109:327–336

    Article  CAS  PubMed  Google Scholar 

  • Stalmans I, et al. (2003) VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nat Med 9:173–182

    Article  CAS  PubMed  Google Scholar 

  • 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 99:9656–9661

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, et al. (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:1843–1851

    Article  CAS  PubMed  Google Scholar 

  • Tordjman R, et al. (2001) Erythroblasts are a source of angiogenic factors. Blood 97:1968–1974

    Article  CAS  PubMed  Google Scholar 

  • Torry DS, et al. (1996) Vascular endothelial growth factor expression in cycling human endometrium. Fertil Steril 66:72–80

    CAS  PubMed  Google Scholar 

  • Visvader JE, Fujiwara Y, Orkin SH (1998) Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development. Genes Dev 12:473–479

    CAS  PubMed  Google Scholar 

  • Vitelli F, et al. (2002) Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Hum Mol Genet 11:915–922

    Article  CAS  PubMed  Google Scholar 

  • 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 91 695–704

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Yancopoulos GD, et al. (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    CAS  PubMed  Google Scholar 

  • Zelzer E, et al. (2002) Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129:1893–1904

    CAS  PubMed  Google Scholar 

  • 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 387:537–546

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, et al. (2002) beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 129:2891–2903

    CAS  PubMed  Google Scholar 

  • Zhu Y, et al. (2003) Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J 17:186–193

    Article  CAS  PubMed  Google Scholar 

  • Ziegler BL, et al. (1999) KDR receptor: a key marker defining hematopoietic stem cells. Science 285:1553–1558

    Article  CAS  PubMed  Google Scholar 

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  1. The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, 3000, Leuven, Belgium

    Marc Tjwa, Aernout Luttun, Monica Autiero & Peter Carmeliet

  2. The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Campus Gasthuisberg, Herestraat 49, 3000, Leuven, Belgium

    Peter Carmeliet

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  1. Marc Tjwa
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  2. Aernout Luttun
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  3. Monica Autiero
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  4. Peter Carmeliet
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Correspondence to Peter Carmeliet.

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Tjwa, M., Luttun, A., Autiero, M. et al. VEGF and PlGF: two pleiotropic growth factors with distinct roles in development and homeostasis. Cell Tissue Res 314, 5–14 (2003). https://doi.org/10.1007/s00441-003-0776-3

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