Alternative titles; symbols
HGNC Approved Gene Symbol: PGF
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:74,941,830-74,955,764 (from NCBI)
The PGF gene encodes placenta growth factor, a homolog of vascular endothelial growth factor (VEGFA; 192240), that selectively binds to VEGFR1 (FLT1; 165070) and is involved in angiogenesis (Fischer et al., 2007; Bais et al., 2010).
Maglione et al. (1991) isolated a human cDNA encoding a protein related to the vascular permeability factor (VPF; also VEGF; 192240). The protein, symbolized PLGF by them, is 149 amino acids long and shares 53% identity with the platelet-derived growth factor-like region of human VPF. They showed that the N-glycosylated PLGF protein is secreted into the medium and that it functions as a dimer.
Mattei et al. (1996) stated that VEGF and PLGF constitute a family of regulatory peptides capable of controlling blood vessel formation and permeability by interacting with 2 endothelial tyrosine kinase receptors, FLT1 (165070) and KDR/FLK1 (191306).
There are 3 isoforms of PGF, designated PGF1, PGF2, and PGF3. Only PGF2 is able to bind heparin. Migdal et al. (1998) found that PGF2 bound neuropilin-1 (NRP1; 602069) in human umbilical vein endothelial cells in a heparin-dependent fashion. Sulfation of the glucosamine-O-6 and iduronic acid-O-2 groups of heparin potentiated PGF2 binding to NRP1. NRP1 also bound PGF1 with lower affinity.
Luttun et al. (2002) reported experiments bearing on the therapeutic potential of PLGF and its receptor FLT1 in angiogenesis. They reported that PLGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to VEGF. An antibody against FLT1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-FLT1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor FLK1 did not affect arthritis or atherosclerosis, indicating that inhibition of FLK1-driven angiogenesis alone is not sufficient to halt disease progression. The antiinflammatory effects of anti-FLT1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of FLT1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PLGF and FLT1 were considered potential candidates for therapeutic modulation of angiogenesis and inflammation.
Autiero et al. (2003) reported that PGF regulates inter- and intramolecular cross-talk between the VEGF receptor tyrosine kinases FLT1 and FLK1. Activation of FLT1 by PGF resulted in intermolecular transphosphorylation of FLK1, thereby amplifying VEGF-driven angiogenesis through FLK1. Even though VEGF and PGF both bind FLT1, PGF uniquely stimulated the phosphorylation of specific FLT1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor cross-talk through formation of FLK1/FLT1 heterodimers. Autiero et al. (2003) concluded that the inter- and intramolecular VEGF receptor cross-talk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone.
In preeclamptic women, Maynard et al. (2003) found increased soluble FLT1 (sFLT1) associated with decreased circulating levels of free VEGF and PGF, resulting in endothelial dysfunction in vitro that was rescued by exogenous VEGF and PGF. Administration of sFLT1 to pregnant rats induced hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. Maynard et al. (2003) suggested that excess circulating sFLT1 contributes to the pathogenesis of preeclampsia.
In 120 preeclamptic women and 120 matched, normotensive controls, Levine et al. (2004) measured serum levels of the angiogenic factors sFLT1, PGF, and VEGF throughout pregnancy. Beginning at 13 to 16 weeks of gestation, PGF levels were significantly lower in women who later had preeclampsia than in controls (p = 0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with an increase in the sFLT1 level which was also more pronounced in the preeclamptic women. Levine et al. (2004) concluded that increased levels of sFLT1 and reduced levels of PGF predict the subsequent development of preeclampsia.
PGF upregulates expression of endothelin-1 (ET1; 131240) via HIF1-alpha (HIF1A; 603348). Using primary human endothelial cells and cell lines, Li et al. (2015) found that PGF also upregulated ET1 via a pathway involving PAX5 (167414) and microRNA-648 (MIR648; 616205). They showed that MIR648 directly targeted the 3-prime UTR of ET1 and destabilized the transcript, thereby reducing ET1 translation. Overexpression and knockdown studies revealed that PGF indirectly reduced MIR648 content by downregulating PAX5, a positive regulator of MIR648 expression.
Mattei et al. (1996) used radioactive chromosomal in situ hybridization to map the PGF gene to 14q24-q31.
Carmeliet et al. (2001) developed Pgf-deficient mice by targeted disruption. Pgf -/- mice were born at expected mendelian ratios and were viable and fertile. Pgf -/- mice had subtle changes of VEGF-dependent retinal and luteal angiogenesis. Pgf -/- mice manifested impaired angiogenesis, plasma extravasation, and collateral growth during ischemia, inflammation, wound healing, and cancer. Transplantation of wildtype bone marrow rescued the impaired angiogenesis and collateral growth in Pgf -/- mice, indicating that PGF might have contributed to vessel growth in the adult by mobilizing bone marrow-derived cells. The synergism between PGF and VEGF was specific, as PGF deficiency impaired the response to VEGF, but not to FGF (131220) or histamine. VEGFR1 was activated by PGF, given that anti-VEGFR1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PGF or VEGF/PLGF. By upregulating PGF and the signaling subtype of VEGFR1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathologic disorders.
Maes et al. (2006) found that Plgf expression was upregulated during healing of semistabilized bone fractures in wildtype mice. Upregulation began at postfracture day 2 and increased to maximal at postfracture day 10, during the transition between soft and hard callus phases of repair. Plgf-null mice showed altered bone repair leading to delayed unions. There was massive accumulation of cartilage in the callus and reduced inflammatory response and vascularization of the fracture wound. In addition, Plgf deletion affected subsequent stages of repair, including proliferation and osteogenic differentiation of mesenchymal progenitors, cartilage turnover by matrix metalloproteases (see MMP1; 120353), and osteoclast differentiation. Maes et al. (2006) concluded that PLGF is required for mediating and coordinating numerous aspects of bone fracture repair.
Carnevale et al. (2014) found that the progressive rise in blood pressure observed in wildtype mice following chronic infusion of angiotensin II (106150) was abolished in Plgf -/- mice. There was no difference in heart rate between wildtype and Plgf -/- mice both under basal conditons and after angiotensin II infusion. Wildtype mice exhibited a marked infiltration of Cd8 (see 186910)-positive and Cd4 (186940)-positive T cells in vessels and kidneys following angiotensin II infusion, but these lymphocytes were absent in Plgf -/- tissues. Plgf -/- mice also showed lower immune system activation and T-cell egress from spleen compared with wildtype mice. The authors noted that mice subjected to celiac ganglionectomy show markedly attenuated angiotensin II-induced hypertension. They observed a significantly reduced number of T cells in aortas and kidneys of wildtype mice subjected to celiac ganglionectomy during the prehypertensive phase of angiotensin II infusion. Spleen transplantation experiments confirmed the splenic origin of infiltrating T cells and the necessity of Plgf for the onset of hypertension. Further experiments showed that Plgf regulated expression of Timp3 (188826) via the transcriptional Sirt1 (604479)-p53 (191170) axis. Carnevale et al. (2014) concluded that PLGF mediates neuroimmune interaction in the spleen, organizing a unique and nonredundant response that allows the onset of hypertension.
Therapeutic Strategies
Fischer et al. (2007) found that a neutralizing murine anti-Plgf monoclonal antibody that specifically recognized mouse Plgf2 inhibited binding to Vegfr1 without inhibiting the binding or activity of Vegf. In mice, the anti-Plgf antibody dose-dependently inhibited tumor growth and local tumor invasion in 12 different solid tumor models tested by 55 to 66%. The antibody inhibited the growth of Vegfr inhibitor-sensitive and Vegfr inhibitor-resistant tumors, and enhanced the tumor growth inhibitory effect of cytostatic agents. Anti-Plgf antibody acted by inhibiting angiogenesis, lymphangiogenesis, tumor cell motility, and inflammation.
In contrast, Bais et al. (2010) found that 4 different anti-Plgf antibodies did not inhibit angiogenesis during primary tumor growth in mice. Anti-Plgf antibodies also did not decrease microvascular density or inflammation, but did inhibit wound healing and blocked growth of Vegfr1-overexpressing tumors, indicating that they were effective at blocking Plgf activity.
In a response to the study by Bais et al. (2010), Van de Veire et al. (2010) reported that the formation of skin papillomas and neovessels was delayed in Plgf-null mice compared to wildtype mice in a carcinogen-induced skin epithelial tumor model. Anti-Plgf antibody showed antitumor activity in human pancreatic xenografts, and blockade of Plgf reduced hepatocellular carcinoma growth in mice by inhibiting angiogenesis. Anti-Plgf antibody also inhibited choroidal neovascularization in ocular disease.
Autiero, M., Waltenberger, J., Communi, D., Kranz, A., Moons, L., Lambrechts, D., Kroll, J., Plaisance, S., De Mol, M., Bono, F., Kliche, S., Fellbrich, G., and 16 others. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature Med. 9: 936-943, 2003. [PubMed: 12796773] [Full Text: https://doi.org/10.1038/nm884]
Bais, C., Wu, X., Yao, J., Yang, S., Crawford, Y., McCutcheon, K., Tan, C., Kolumam, G., Vernes, J.-M., Eastham-Anderson, J., Haughney, P., Kowanetz, M., and 11 others. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141: 166-177, 2010. [PubMed: 20371352] [Full Text: https://doi.org/10.1016/j.cell.2010.01.033]
Carmeliet, P., Moons, L., Luttun, A., Vincenti, V., Compernolle, V., De Mol, M., Wu, Y., Bono, F., Devy, L., Beck, H., Scholz, D., Acker, T., and 17 others. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature Med. 7: 575-583, 2001. [PubMed: 11329059] [Full Text: https://doi.org/10.1038/87904]
Carnevale, D., Pallante, F., Fardella, V., Fardella, S., Iacobucci, R., Federici, M., Cifelli, G., De Lucia, M., Lembo, G. The angiogenic factor PlGF mediates a neuroimmune interaction in the spleen to allow the onset of hypertension. Immunity 41: 737-752, 2014. [PubMed: 25517614] [Full Text: https://doi.org/10.1016/j.immuni.2014.11.002]
Fischer, C., Jonckx, B., Mazzone, M., Zacchigna, S., Loges, S., Pattarini, L., Chorianopoulos, E., Liesenborghs, L., Koch, M., De Mol, M., Autiero, M., Wyns, S., Plaisance, S., Moons, L., van Rooijen, N., Giacca, M., Stassen, J. M., Dewerchin, M., Collen, D., Carmeliet, P. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131: 463-475, 2007. [PubMed: 17981115] [Full Text: https://doi.org/10.1016/j.cell.2007.08.038]
Levine, R. J., Maynard, S. E., Qian, C., Lim, K.-H., England, L. J., Yu, K. F., Schisterman, E. F., Thadhani, R., Sachs, B. P., Epstein, F. H, Sibai, B. M., Sukhatme, V. P., Karumanchi, S. A. Circulating angiogenic factors and the risk of preeclampsia. New Eng. J. Med. 350: 672-683, 2004. [PubMed: 14764923] [Full Text: https://doi.org/10.1056/NEJMoa031884]
Li, C., Gonsalves, C. S., Eiymo Mwa Mpollo, M.-S., Malik, P., Tahara, S. M., Kalra, V. K. MicroRNA 648 targets ET-1 mRNA and is cotranscriptionally regulated with MICAL3 by PAX5. Molec. Cell. Biol. 35: 514-528, 2015. [PubMed: 25403488] [Full Text: https://doi.org/10.1128/MCB.01199-14]
Luttun, A., Tjwa, M., Moons, L., Wu, Y., Angelillo-Scherrer, A., Liao, F., Nagy, J. A., Hooper, A., Priller, J., De Klerck, B., Compernolle, V., Daci, E., and 10 others. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nature Med. 8: 831-840, 2002. [PubMed: 12091877] [Full Text: https://doi.org/10.1038/nm731]
Maes, C., Coenegrachts, L., Stockmans, I., Daci, E., Luttun, A., Petryk, A., Gopalakrishnan, R., Moermans, K., Smets, N., Verfaillie, C. M., Carmeliet, P., Bouillon, R., Carmeliet, G. Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair. J. Clin. Invest. 116: 1230-1242, 2006. [PubMed: 16614757] [Full Text: https://doi.org/10.1172/JCI26772]
Maglione, D., Guerriero, V., Viglietto, G., Delli-Bovi, P., Persico, M. G. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Nat. Acad. Sci. 88: 9267-9271, 1991. [PubMed: 1924389] [Full Text: https://doi.org/10.1073/pnas.88.20.9267]
Mattei, M.-G., Borg, J.-P., Rosnet, O., Marme, 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: 168-169, 1996. [PubMed: 8786112] [Full Text: https://doi.org/10.1006/geno.1996.0098]
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. 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, 2003. [PubMed: 12618519] [Full Text: https://doi.org/10.1172/JCI17189]
Migdal, M., Huppertz, B., Tessler, S., Comforti, A., Shibuya, M., Reich, R., Baumann, H., Neufeld, G. Neuropilin-1 is a placenta growth factor-2 receptor. J. Biol. Chem. 273: 22272-22278, 1998. [PubMed: 9712843] [Full Text: https://doi.org/10.1074/jbc.273.35.22272]
Van de Veire, S., Stalmans, I., Heindryckx, F., Oura, H., Tijeras-Raballand, A., Schmidt, T., Loges, S., Albrecht, I., Jonckx, B., Vinckier, S., Van Steenkiste, C., Tugues, S., and 39 others. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141: 178-190, 2010. [PubMed: 20371353] [Full Text: https://doi.org/10.1016/j.cell.2010.02.039]