Placental growth factor explained

Placental growth factor (PlGF) is a protein that in humans is encoded by the PGF gene.^{[1] [2]}

Placental growth factor (PGF) is a member of the VEGF (vascular endothelial growth factor) sub-family - a key molecule in angiogenesis and vasculogenesis, in particular during embryogenesis. The main source of PGF during pregnancy is the placental trophoblast. PGF is also expressed in many other tissues, including the villous trophoblast.^[3]

The placental growth factor (PGF) gene is a protein-coding gene and a member of the vascular endothelial growth factor (VEGF) family. The PGF gene is expressed only in human umbilical vein endothelial cells (HUVE) and the placenta. PGF is ultimately associated with angiogenesis. Specifically, PGF plays a role in trophoblast growth and differentiation. Trophoblast cells, specifically extravillous trophoblast cells, are responsible for invading the uterine wall and the maternal spiral arteries. The extravillous trophoblast cells produce a blood vessel of larger diameter for the developing fetus that is independent of maternal vasoconstriction. This is essential for increased blood flow and reduced resistance.^[4] Proper development of blood vessels in the placenta is crucial for the higher blood requirement of the fetus later in pregnancy. Under normal physiologic conditions, PGF is also expressed at a low level in other organs including the heart, lung, thyroid, and skeletal muscle.

Isoform tissue specificity

There are three isoforms of this protein: PGF-1, PGF-2, PGF-3. PGF-1 is specifically found in the colon as well as mammary carcinomas, while PGF-2 is only found in early placenta up until the 8th week of development. PGF-2 is the only isoform able to bind to heparin. PGF-3 is found mainly in placental tissues. ^{[5] [6]}

Clinical significance

Placental growth factor-expression within human atherosclerotic lesions is associated with plaque inflammation and neovascular growth.^{[7] [8]}

Serum levels of PGF and sFlt-1 (soluble fms-like tyrosine kinase-1, also known as soluble VEGF receptor-1) are altered in women with preeclampsia. Studies show that in both early and late onset preeclampsia, maternal serum levels of sFlt-1 are higher and PGF lower in women presenting with preeclampsia. In addition, placental sFlt-1 levels were significantly increased and PGF decreased in women with preeclampsia as compared to those with uncomplicated pregnancies. This suggests that placental concentrations of sFlt-1 and PGF mirror the maternal serum changes. This is consistent with the view that the placenta is the main source of sFlt-1 and PGF during pregnancy.¹

PGF is a potential biomarker for preeclampsia, a condition in which blood vessels in the placenta are too narrow, resulting in high blood pressure. As mentioned before, extravillous trophoblast cells invade maternal arteries. Improper differentiation may result in hypo-invasion of these arteries and thus failure to widen enough. Studies have found low levels of PGF in women who were diagnosed with preeclampsia later in their pregnancy.

Associated diseases

Placental insufficiency, otherwise known as uteroplacental vascular insufficiency, results from insufficient blood supply to the placenta. This disease is characterized by an alteration in the PGF gene and its GPCR and ERK signaling pathways.^[9] Alterations in the PGF and the PGF receptor mRNA expression prevent the normal development of placental vasculature.^[10]

Twin-to-twin transfusion syndrome is another disease associated with the PGF gene. This is a rare disease occurring primarily in identical twins where blood from one twin is transferred to the other. Typically, the twin whose blood is being transferred is born smaller and with anemia while the other twin is born larger with too much blood and at increased risk for heart failure. The PGF gene pathways primarily affected are the TGF-Beta pathway and AKT signaling pathway.^[11]

Further reading

• De Falco S . The discovery of placenta growth factor and its biological activity . Experimental & Molecular Medicine . 44 . 1 . 1–9 . January 2012 . 22228176 . 3277892 . 10.3858/emm.2012.44.1.025 .
• Luttun A, Tjwa M, Carmeliet P . Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders . Annals of the New York Academy of Sciences . 979 . 80–93 . December 2002 . 12543719 . 10.1111/j.1749-6632.2002.tb04870.x . 73356935 .
• Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG . Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor . Proceedings of the National Academy of Sciences of the United States of America . 88 . 20 . 9267–71 . October 1991 . 1924389 . 52695 . 10.1073/pnas.88.20.9267 . 1991PNAS...88.9267M . free .
• Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG . Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14 . Oncogene . 8 . 4 . 925–31 . April 1993 . 7681160 .
• Park JE, Chen HH, Winer J, Houck KA, Ferrara N . 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 . The Journal of Biological Chemistry . 269 . 41 . 25646–54 . October 1994 . 10.1016/S0021-9258(18)47298-5 . 7929268 . free .
• Hauser S, Weich HA . A heparin-binding form of placenta growth factor (PlGF-2) is expressed in human umbilical vein endothelial cells and in placenta . Growth Factors . 9 . 4 . 259–68 . 1994 . 8148155 . 10.3109/08977199308991586 .
• Mattei MG, Borg JP, Rosnet O, Marmé D, Birnbaum D . Assignment of vascular endothelial growth factor (VEGF) and placenta growth factor (PLGF) genes to human chromosome 6p12-p21 and 14q24-q31 regions, respectively . Genomics . 32 . 1 . 168–9 . February 1996 . 8786112 . 10.1006/geno.1996.0098 .
• Ziche M, Maglione D, Ribatti D, Morbidelli L, Lago CT, Battisti M, Paoletti I, Barra A, Tucci M, Parise G, Vincenti V, Granger HJ, Viglietto G, Persico MG . Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic . Laboratory Investigation; A Journal of Technical Methods and Pathology . 76 . 4 . 517–31 . April 1997 . 9111514 .
• Vuorela P, Hatva E, Lymboussaki A, Kaipainen A, Joukov V, Persico MG, Alitalo K, Halmesmäki E . Expression of vascular endothelial growth factor and placenta growth factor in human placenta . Biology of Reproduction . 56 . 2 . 489–94 . February 1997 . 9116151 . 10.1095/biolreprod56.2.489 . free .
• Cao Y, Ji WR, Qi P, Rosin A, Cao Y . Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing . Biochemical and Biophysical Research Communications . 235 . 3 . 493–8 . June 1997 . 9207183 . 10.1006/bbrc.1997.6813 .
• Davis-Smyth T, Presta LG, Ferrara N . Mapping the charged residues in the second immunoglobulin-like domain of the vascular endothelial growth factor/placenta growth factor receptor Flt-1 required for binding and structural stability . The Journal of Biological Chemistry . 273 . 6 . 3216–22 . February 1998 . 9452434 . 10.1074/jbc.273.6.3216 . free .
• Landgren E, Schiller P, Cao Y, Claesson-Welsh L . Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1 . Oncogene . 16 . 3 . 359–67 . January 1998 . 9467961 . 10.1038/sj.onc.1201545 . free .
• Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G . Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected] . The Journal of Biological Chemistry . 275 . 24 . 18040–5 . June 2000 . 10748121 . 10.1074/jbc.M909259199 . free .
• Renedo M, Arce I, Montgomery K, Roda-Navarro P, Lee E, Kucherlapati R, Fernández-Ruiz E . A sequence-ready physical map of the region containing the human natural killer gene complex on chromosome 12p12.3-p13.2 . Genomics . 65 . 2 . 129–36 . April 2000 . 10783260 . 10.1006/geno.2000.6163 .
• Maglione D, Battisti M, Tucci M . Recombinant production of PIGF-1 and its activity in animal models . Farmaco . 55 . 3 . 165–7 . March 2000 . 10919072 . 10.1016/S0014-827X(00)00012-4 .
• Roberts-Clark DJ, Smith AJ . Angiogenic growth factors in human dentine matrix . Archives of Oral Biology . 45 . 11 . 1013–6 . November 2000 . 11000388 . 10.1016/S0003-9969(00)00075-3 .
• Iyer S, Leonidas DD, Swaminathan GJ, Maglione D, Battisti M, Tucci M, Persico MG, Acharya KR . The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 A resolution . The Journal of Biological Chemistry . 276 . 15 . 12153–61 . April 2001 . 11069911 . 10.1074/jbc.M008055200 . free .
• Li XF, Charnock-Jones DS, Zhang E, Hiby S, Malik S, Day K, Licence D, Bowen JM, Gardner L, King A, Loke YW, Smith SK . Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells . The Journal of Clinical Endocrinology and Metabolism . 86 . 4 . 1823–34 . April 2001 . 10.1210/jcem.86.4.7418 . 11297624 . free .
• Su YN, Hsu JJ, Lee CN, Cheng WF, Kung CC, Hsieh FJ . Raised maternal serum placenta growth factor concentration during the second trimester is associated with Down syndrome . Prenatal Diagnosis . 22 . 1 . 8–12 . January 2002 . 11810642 . 10.1002/pd.218 . 25971596 .
• Angelucci C, Lama G, Iacopino F, Maglione D, Sica G . Effect of placenta growth factor-1 on proliferation and release of nitric oxide, cyclic AMP and cyclic GMP in human epithelial cells expressing the FLT-1 receptor . Growth Factors . 19 . 3 . 193–206 . 2002 . 11811792 . 10.3109/08977190109001086 . 20716290 .
• Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M . Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain . The Journal of Biological Chemistry . 277 . 27 . 24818–25 . July 2002 . 11986311 . 10.1074/jbc.M200730200 . free .

Notes and References

1. Web site: Entrez Gene: PGF placental growth factor, vascular endothelial growth factor-related protein.
2. Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG . Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14 . Oncogene . 8 . 4 . 925–31 . April 1993 . 7681160 .
3. Khalil A, Muttukrishna S, Harrington K, Jauniaux E . Effect of antihypertensive therapy with alpha methyldopa on levels of angiogenic factors in pregnancies with hypertensive disorders . PLOS ONE . 3 . 7 . e2766 . July 2008 . 18648513 . 2447877 . 10.1371/journal.pone.0002766 . 2008PLoSO...3.2766K . Lumbiganon . Pisake . free .
4. Book: Carlson . Bruce . Human Embryology and Developmental Biology . 2009 . Elsevier . 978-0-323-05385-3.
5. Web site: UniProtKB - P49763 (PLGF_HUMAN). UniProt.
6. Web site: Placental Growth Factor. Online Mendelian Inheritance in Man.
7. Khurana R, Moons L, Shafi S, Luttun A, Collen D, Martin JF, Carmeliet P, Zachary IC . Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation . Circulation . 111 . 21 . 2828–36 . May 2005 . 15911697 . 10.1161/CIRCULATIONAHA.104.495887 . free .
8. Shibuya M . Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis . BMB Reports . 41 . 4 . 278–86 . April 2008 . 18452647 . 10.5483/BMBRep.2008.41.4.278 . free .
9. Web site: Placental Insufficiency. MalaCards.
10. Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR). Placenta. 2002. 11945079. Regnault. T. R.. Orbus. R. J.. De Vrijer. B.. Davidsen. M. L.. Galan. H. L.. Wilkening. R. B.. Anthony. R. V.. 23. 2–3. 132–144. 10.1053/plac.2001.0757.
11. Web site: Twin-to-Twin Transfusion Syndrome. MalaCards.