Placental growth factor

Placental growth factor (PlGF) is a protein that in humans is encoded by the PGF gene.^[5][6]

PGF
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1FZV, 1RV6
Identifiers
Aliases	PGF, D12S1900, PGFL, PLGF, PlGF-2, SHGC-10760, Placental growth factor, PIGF
External IDs	OMIM: 601121 MGI: 105095 HomoloGene: 1978 GeneCards: PGF
Gene location (Human) Chr. Chromosome 14 (human)^[1] Band 14q24.3 Start 74,941,834 bp^[1] End 74,955,626 bp^[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)^[2] Band 12 D1|12 39.58 cM Start 85,213,409 bp^[2] End 85,224,564 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in renal medulla cardia pylorus nipple ventral tegmental area trigeminal ganglion inferior ganglion of vagus nerve external globus pallidus superior surface of tongue subthalamic nucleus Top expressed in external carotid artery ankle joint internal carotid artery facial motor nucleus saccule mirror islet of Langerhans ectoderm Bowman's capsule lacrimal gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function heparin binding protein homodimerization activity protein binding protein heterodimerization activity growth factor activity vascular endothelial growth factor receptor binding chemoattractant activity vascular endothelial growth factor receptor 3 binding Cellular component membrane extracellular region extracellular space Biological process cell differentiation female pregnancy cell-cell signaling regulation of morphogenesis of a branching structure sprouting angiogenesis multicellular organism development branching involved in ureteric bud morphogenesis cellular response to hormone stimulus animal organ regeneration positive regulation of cell population proliferation positive regulation of cell division signal transduction angiogenesis response to hypoxia positive regulation of endothelial cell proliferation positive regulation of angiogenesis vascular endothelial growth factor receptor signaling pathway induction of positive chemotaxis positive regulation of mast cell chemotaxis regulation of signaling receptor activity positive regulation of protein phosphorylation vascular endothelial growth factor signaling pathway positive chemotaxis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5228 18654 Ensembl ENSG00000119630 ENSMUSG00000004791 UniProt P49763 P49764 RefSeq (mRNA) NM_002632 NM_001207012 NM_001293643 NM_001271705 NM_008827 RefSeq (protein) NP_001193941 NP_001280572 NP_002623 NP_001258634 NP_032853 Location (UCSC) Chr 14: 74.94 – 74.96 Mb Chr 12: 85.21 – 85.22 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[7]

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.^[8] 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. ^{[9] [10]}

Clinical significance

Placental growth factor-expression within human atherosclerotic lesions is associated with plaque inflammation and neovascular growth.^[11][12]

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.^[13] Alterations in the PGF and the PGF receptor mRNA expression prevent the normal development of placental vasculature.^[14]

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.^[15]

References

1. GRCh38: Ensembl release 89: ENSG00000119630 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000004791 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: PGF placental growth factor, vascular endothelial growth factor-related protein".
6. Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG (April 1993). "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. PMID 7681160.
7. Khalil A, Muttukrishna S, Harrington K, Jauniaux E (July 2008). Lumbiganon P (ed.). "Effect of antihypertensive therapy with alpha methyldopa on levels of angiogenic factors in pregnancies with hypertensive disorders". PLOS ONE. 3 (7): e2766. Bibcode:2008PLoSO...3.2766K. doi:10.1371/journal.pone.0002766. PMC 2447877. PMID 18648513.
8. Carlson, Bruce (2009). Human Embryology and Developmental Biology. Elsevier. ISBN 978-0-323-05385-3.
9. "UniProtKB - P49763 (PLGF_HUMAN)". UniProt.
10. "Placental Growth Factor". Online Mendelian Inheritance in Man.
11. Khurana R, Moons L, Shafi S, Luttun A, Collen D, Martin JF, Carmeliet P, Zachary IC (May 2005). "Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation" (PDF). Circulation. 111 (21): 2828–36. doi:10.1161/CIRCULATIONAHA.104.495887. PMID 15911697.
12. Shibuya M (April 2008). "Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis". BMB Reports. 41 (4): 278–86. doi:10.5483/BMBRep.2008.41.4.278. PMID 18452647.
13. "Placental Insufficiency". MalaCards.
14. Regnault, T. R.; Orbus, R. J.; De Vrijer, B.; Davidsen, M. L.; Galan, H. L.; Wilkening, R. B.; Anthony, R. V. (2002). "Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR)". Placenta. 23 (2–3): 132–144. doi:10.1053/plac.2001.0757. PMID 11945079.
15. "Twin-to-Twin Transfusion Syndrome". MalaCards.

Further reading

• De Falco S (January 2012). "The discovery of placenta growth factor and its biological activity". Experimental & Molecular Medicine. 44 (1): 1–9. doi:10.3858/emm.2012.44.1.025. PMC 3277892. PMID 22228176.
• Luttun A, Tjwa M, Carmeliet P (December 2002). "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. doi:10.1111/j.1749-6632.2002.tb04870.x. PMID 12543719. S2CID 73356935.
• Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG (October 1991). "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. Bibcode:1991PNAS...88.9267M. doi:10.1073/pnas.88.20.9267. PMC 52695. PMID 1924389.
• Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG (April 1993). "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. PMID 7681160.
• Park JE, Chen HH, Winer J, Houck KA, Ferrara N (October 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". The Journal of Biological Chemistry. 269 (41): 25646–54. doi:10.1016/S0021-9258(18)47298-5. PMID 7929268.
• Hauser S, Weich HA (1994). "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. doi:10.3109/08977199308991586. PMID 8148155.
• Mattei MG, Borg JP, Rosnet O, Marmé D, Birnbaum D (February 1996). "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. doi:10.1006/geno.1996.0098. PMID 8786112.
• 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 (April 1997). "Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic". Laboratory Investigation; A Journal of Technical Methods and Pathology. 76 (4): 517–31. PMID 9111514.
• Vuorela P, Hatva E, Lymboussaki A, Kaipainen A, Joukov V, Persico MG, Alitalo K, Halmesmäki E (February 1997). "Expression of vascular endothelial growth factor and placenta growth factor in human placenta". Biology of Reproduction. 56 (2): 489–94. doi:10.1095/biolreprod56.2.489. PMID 9116151.
• Cao Y, Ji WR, Qi P, Rosin A, Cao Y (June 1997). "Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing". Biochemical and Biophysical Research Communications. 235 (3): 493–8. doi:10.1006/bbrc.1997.6813. PMID 9207183.
• Davis-Smyth T, Presta LG, Ferrara N (February 1998). "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. doi:10.1074/jbc.273.6.3216. PMID 9452434.
• Landgren E, Schiller P, Cao Y, Claesson-Welsh L (January 1998). "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. doi:10.1038/sj.onc.1201545. PMID 9467961.
• Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G (June 2000). "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. doi:10.1074/jbc.M909259199. PMID 10748121.
• Renedo M, Arce I, Montgomery K, Roda-Navarro P, Lee E, Kucherlapati R, Fernández-Ruiz E (April 2000). "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. doi:10.1006/geno.2000.6163. PMID 10783260.
• Maglione D, Battisti M, Tucci M (March 2000). "Recombinant production of PIGF-1 and its activity in animal models". Farmaco. 55 (3): 165–7. doi:10.1016/S0014-827X(00)00012-4. PMID 10919072.
• Roberts-Clark DJ, Smith AJ (November 2000). "Angiogenic growth factors in human dentine matrix". Archives of Oral Biology. 45 (11): 1013–6. doi:10.1016/S0003-9969(00)00075-3. PMID 11000388.
• Iyer S, Leonidas DD, Swaminathan GJ, Maglione D, Battisti M, Tucci M, Persico MG, Acharya KR (April 2001). "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. doi:10.1074/jbc.M008055200. PMID 11069911.
• 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 (April 2001). "Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells". The Journal of Clinical Endocrinology and Metabolism. 86 (4): 1823–34. doi:10.1210/jcem.86.4.7418. PMID 11297624.
• Su YN, Hsu JJ, Lee CN, Cheng WF, Kung CC, Hsieh FJ (January 2002). "Raised maternal serum placenta growth factor concentration during the second trimester is associated with Down syndrome". Prenatal Diagnosis. 22 (1): 8–12. doi:10.1002/pd.218. PMID 11810642. S2CID 25971596.
• Angelucci C, Lama G, Iacopino F, Maglione D, Sica G (2002). "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. doi:10.3109/08977190109001086. PMID 11811792. S2CID 20716290.
• Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M (July 2002). "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. doi:10.1074/jbc.M200730200. PMID 11986311.