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Gene Review

PGF  -  placental growth factor

Homo sapiens

Synonyms: D12S1900, PGFL, PLGF, PlGF, PlGF-2, ...
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Disease relevance of PGF

  • Chronic transgenic delivery of PlGF-2 to murine epidermis resulted in a significantly increased inflammatory response, associated with more pronounced vascular enlargement, edema, and inflammatory cell infiltration than seen in wild-type mice [1].
  • Levels of soluble Flt-1 (sFlt-1) protein in supernatant of term villous explants were upregulated by 1 per cent hypoxia, whereas hyperoxia (40 per cent) decreased sFlt-1 levels, indicating that under conditions of increasing oxygen tension, PlGF function may remain unopposed [2].
  • Infection of Sf158 insect cells with recombinant baculoviruses specific for the two forms showed, that both, PlGF-1 and PlGF-2 are secreted efficiently into the supernatant and PlGF-2 can bind with high affinity to heparin [3].
  • In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis [4].
  • Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality [4].

High impact information on PGF

  • Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects [4].
  • These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF) [5].
  • Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery [6].
  • Finally, a conditioned medium from COS-1 cells containing PlGF is capable of stimulating specifically the growth of CPA, a line of endothelial cells, in vitro [7].
  • By using N-glycosidase F, tunicamycin, and specific antibodies produced in both chicken and rabbit, we demonstrate that PlGF, derived from transfected COS-1 cells, is actually N-glycosylated and secreted into the medium [7].

Chemical compound and disease context of PGF


Biological context of PGF

  • These observations indicate that the peptides encoded by these exons probably participate in the formation of the domain which mediates the binding of PlGF-2 to these receptors [11].
  • In competition experiments, VEGF165 competed PlGF-2 binding to the NRP1 b1b2 domain, suggesting that the binding sites of VEGF165 and PlGF-2 overlap [12].
  • Mutagenesis analysis, performed on the basis of a structural model of interaction between PlGF and the minimal binding domain of Flt-1, has led to the identification of several PlGF-1 residues involved in Flt-1 recognition [13].
  • Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are key angiogenic stimulators during normal development and wound healing, as well as in a variety of pathological conditions [14].
  • Tissue distribution analysis of PlGF mRNA expression using microarrays revealed a very restricted expression of PlGF only in BMP-2-treated MSCs and in placenta as expected [15].

Anatomical context of PGF


Associations of PGF with chemical compounds


Physical interactions of PGF


Regulatory relationships of PGF

  • The binding of 125I-PlGF-2 to these receptors was inhibited by an excess of PlGF-2 and by the 165-amino acid form of VEGF (VEGF165), but not at all by VEGF121 and very marginally if at all by PlGF-1 [11].
  • BMP-2 stimulated PlGF expression in MG63 cells with an EC50 of about 50 ng/ml and mRNA levels peaked between 24 and 32 h after stimulation [15].
  • Since PlGF is made by the human placenta and extravillous trophoblast (EV-T) cells of the human placenta express Flt-1 in situ, these cells may be responsive to PlGF [23].
  • PlGF-induced activation of the SAPK signaling pathways protected trophoblast from growth factor withdrawal-induced apoptosis, but it did not protect trophoblast from apoptosis induced by the pro-inflammatory cytokines, interferon gamma and tumor necrosis factor alpha [24].
  • PlGF induced similar activation of Nck and PLC-gamma in trophoblast and HUVEC [25].

Other interactions of PGF

  • Placenta growth factor (PlGF) belongs to the vascular endothelial growth factor (VEGF) family and represents a key regulator of angiogenic events in pathological conditions [13].
  • The apparent molecular weight and the binding characteristics of these receptors correspond to those of the recently identified VEGF165 specific receptor neuropilin-1, and we therefore conclude that neuropilin-1 is a receptor for PlGF-2 [11].
  • Thus, PlGF and Flt-1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation [26].
  • In this study, a mature isoform of the human PlGF protein, PlGF-1, was crystallized as a homodimer in the crystallographic asymmetric unit, and its crystal structure was elucidated at 2.0 A resolution [18].
  • In vitro the cells incorporated VEGF-A into the surrounding extracellular matrix; PlGF was secreted [27].

Analytical, diagnostic and therapeutic context of PGF


  1. A critical role of placental growth factor in the induction of inflammation and edema formation. Oura, H., Bertoncini, J., Velasco, P., Brown, L.F., Carmeliet, P., Detmar, M. Blood (2003) [Pubmed]
  2. Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) and soluble Flt-1 by oxygen--a review. Ahmed, A., Dunk, C., Ahmad, S., Khaliq, A. Placenta (2000) [Pubmed]
  3. A heparin-binding form of placenta growth factor (PlGF-2) is expressed in human umbilical vein endothelial cells and in placenta. Hauser, S., Weich, H.A. Growth Factors (1993) [Pubmed]
  4. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. Yano, K., Liaw, P.C., Mullington, J.M., Shih, S.C., Okada, H., Bodyak, N., Kang, P.M., Toltl, L., Belikoff, B., Buras, J., Simms, B.T., Mizgerd, J.P., Carmeliet, P., Karumanchi, S.A., Aird, W.C. J. Exp. Med. (2006) [Pubmed]
  5. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. Kaipainen, A., Korhonen, J., Pajusola, K., Aprelikova, O., Persico, M.G., Terman, B.I., Alitalo, K. J. Exp. Med. (1993) [Pubmed]
  6. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Maynard, S.E., Min, J.Y., Merchan, J., Lim, K.H., Li, J., Mondal, S., Libermann, T.A., Morgan, J.P., Sellke, F.W., Stillman, I.E., Epstein, F.H., Sukhatme, V.P., Karumanchi, S.A. J. Clin. Invest. (2003) [Pubmed]
  7. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Maglione, D., Guerriero, V., Viglietto, G., Delli-Bovi, P., Persico, M.G. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  8. Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Adini, A., Kornaga, T., Firoozbakht, F., Benjamin, L.E. Cancer Res. (2002) [Pubmed]
  9. Low urinary placental growth factor is a marker of pre-eclampsia. Aggarwal, P.K., Jain, V., Sakhuja, V., Karumanchi, S.A., Jha, V. Kidney Int. (2006) [Pubmed]
  10. Intracellular pathways triggered by the selective FLT-1-agonist placental growth factor in vascular smooth muscle cells exposed to hypoxia. Bellik, L., Vinci, M.C., Filippi, S., Ledda, F., Parenti, A. Br. J. Pharmacol. (2005) [Pubmed]
  11. Neuropilin-1 is a placenta growth factor-2 receptor. Migdal, M., Huppertz, B., Tessler, S., Comforti, A., Shibuya, M., Reich, R., Baumann, H., Neufeld, G. J. Biol. Chem. (1998) [Pubmed]
  12. Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain. Mamluk, R., Gechtman, Z., Kutcher, M.E., Gasiunas, N., Gallagher, J., Klagsbrun, M. J. Biol. Chem. (2002) [Pubmed]
  13. Identification of placenta growth factor determinants for binding and activation of Flt-1 receptor. Errico, M., Riccioni, T., Iyer, S., Pisano, C., Acharya, K.R., Persico, M.G., De Falco, S. J. Biol. Chem. (2004) [Pubmed]
  14. Upregulation of placental growth factor by vascular endothelial growth factor via a post-transcriptional mechanism. Yao, Y.G., Yang, H.S., Cao, Z., Danielsson, J., Duh, E.J. FEBS Lett. (2005) [Pubmed]
  15. Bone morphogenetic protein 2 induces placental growth factor in mesenchymal stem cells. Marrony, S., Bassilana, F., Seuwen, K., Keller, H. Bone (2003) [Pubmed]
  16. Inhibition of breast carcinoma and trophoblast cell invasiveness by vascular endothelial growth factor. Fitzpatrick, T.E., Lash, G.E., Yanaihara, A., Charnock-Jones, D.S., Macdonald-Goodfellow, S.K., Graham, C.H. Exp. Cell Res. (2003) [Pubmed]
  17. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. Tsatsaris, V., Goffin, F., Munaut, C., Brichant, J.F., Pignon, M.R., Noel, A., Schaaps, J.P., Cabrol, D., Frankenne, F., Foidart, J.M. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  18. The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 A resolution. Iyer, S., Leonidas, D.D., Swaminathan, G.J., Maglione, D., Battisti, M., Tucci, M., Persico, M.G., Acharya, K.R. J. Biol. Chem. (2001) [Pubmed]
  19. Evidence of a novel isoform of placenta growth factor (PlGF-4) expressed in human trophoblast and endothelial cells. Yang, W., Ahn, H., Hinrichs, M., Torry, R.J., Torry, D.S. J. Reprod. Immunol. (2003) [Pubmed]
  20. The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1. Christinger, H.W., Fuh, G., de Vos, A.M., Wiesmann, C. J. Biol. Chem. (2004) [Pubmed]
  21. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Miyamoto, N., de Kozak, Y., Jeanny, J.C., Glotin, A., Mascarelli, F., Massin, P., BenEzra, D., Behar-Cohen, F. Diabetologia (2007) [Pubmed]
  22. Heterodimers of placenta growth factor/vascular endothelial growth factor. Endothelial activity, tumor cell expression, and high affinity binding to Flk-1/KDR. Cao, Y., Chen, H., Zhou, L., Chiang, M.K., Anand-Apte, B., Weatherbee, J.A., Wang, Y., Fang, F., Flanagan, J.G., Tsang, M.L. J. Biol. Chem. (1996) [Pubmed]
  23. Role of placenta growth factor (PIGF) in human extravillous trophoblast proliferation, migration and invasiveness. Athanassiades, A., Lala, P.K. Placenta (1998) [Pubmed]
  24. Signal transduction and biological function of placenta growth factor in primary human trophoblast. Desai, J., Holt-Shore, V., Torry, R.J., Caudle, M.R., Torry, D.S. Biol. Reprod. (1999) [Pubmed]
  25. Deferential regulation of placenta growth factor (PlGF)-mediated signal transduction in human primary term trophoblast and endothelial cells. Arroyo, J., Torry, R.J., Torry, D.S. Placenta (2004) [Pubmed]
  26. Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Luttun, A., Tjwa, M., Carmeliet, P. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  27. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Zhou, Y., McMaster, M., Woo, K., Janatpour, M., Perry, J., Karpanen, T., Alitalo, K., Damsky, C., Fisher, S.J. Am. J. Pathol. (2002) [Pubmed]
  28. Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. Helske, S., Vuorela, P., Carpén, O., Hornig, C., Weich, H., Halmesmäki, E. Mol. Hum. Reprod. (2001) [Pubmed]
  29. Granulocyte/macrophage colony-stimulating factor treatment of human chronic ulcers promotes angiogenesis associated with de novo vascular endothelial growth factor transcription in the ulcer bed. Cianfarani, F., Tommasi, R., Failla, C.M., Viviano, M.T., Annessi, G., Papi, M., Zambruno, G., Odorisio, T. Br. J. Dermatol. (2006) [Pubmed]
  30. Human retinal epithelium produces and responds to placenta growth factor. Hollborn, M., Tenckhoff, S., Seifert, M., Köhler, S., Wiedemann, P., Bringmann, A., Kohen, L. Graefes Arch. Clin. Exp. Ophthalmol. (2006) [Pubmed]
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