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

• The vascular endothelial growth factor (VEGF)-related factor, placental growth factor (PlGF),has been shown recently to play an important role in pathological VEGF-driven angiogenesis.In this study, we examine the effects of mPlGF/PlGF-2 overexpression in tumors grown from glioma cells containing a tetracycline-regulated mPlGF cDNA [8].
• We measured urinary PlGF and creatinine values in 69 pregnant women (35 with pre-eclampsia and 34 normotensive controls) [9].
• Since hypoxia was able to reverse the vasorelaxant effect of PlGF into a vasoconstrictor response, the mechanism of this latter effect was also investigated [10].

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

• Furthermore, neither PlGF-1 nor PlGF-2 had any effect upon the proliferation of the endothelial cells [11].
• Both cell lines also expressed transcripts for VEGF-A, -B, -C and -D, as well as for placenta growth factor (PlGF) [16].
• The mRNA levels of VEGF-A, PlGF, and their receptors were quantified in placentas and placental beds [17].
• Based on the known function of PlGF in the recruitment of endothelial and hematopoietic stem cells, these results suggest a paracrine role for MSC-derived PlGF in the angiogenesis and hematopoiesis that accompany BMP-2-induced bone formation [15].
• The addition of PlGF-1 to a spontaneously transformed first trimester cytotrophoblast cell line (ED27) stimulated cell proliferation while PlGF-2 had little effect [2].

Associations of PGF with chemical compounds

• Heparin enhanced the binding of both 125I-VEGF165 and 125I-PlGF-2 to the b1b2 domain by 20- and 4-fold, respectively [12].
• The angiogenic molecule placenta growth factor (PlGF) is a member of the cysteine-knot family of growth factors [18].
• We have also determined, using chemically modified heparin species, that the presence of sulfate moieties on the glucosamine-O-6 and on the iduronic acid-O-2 groups of heparin was required for the potentiation of 125I-PlGF-2 binding to these receptors [11].
• Placenta growth factor (PlGF), a homodimeric glycoprotein that is homologous to vascular endothelial growth factor (VEGF), is mitogenic to endothelial cells and protects trophoblast from apoptosis [19].
• PlGF exerts its biological activities through binding to VEGFR1, a receptor tyrosine kinase that consists of seven immunoglobulin-like domains in its extracellular portion [20].
• Exposure of ARPE-19 cells to hypoxic conditions or to insulin induced an upregulation of PLGF-1 expression along with increased transcellular permeability [21].

Physical interactions of PGF

• Cross-linking of 125I-ligands to human umbilical vein endothelial cells reveals that PLGF/VEGF heterodimers and VEGF165 homodimers, but not PLGF129 homodimers, form complexes with membrane receptors [22].

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

• We have utilized RT-PCR to characterize PlGF isoform expression in normal human trophoblast and umbilical vein endothelial cells (HUVEC) [19].
• We have studied the localization of these proteins by immunohistochemistry and Western blotting in the placenta and of PlGF in maternal serum, and their association with diabetes, pre-eclampsia, fetal growth restriction (FGR) and fetal alcohol syndrome (FAS) [28].
• PlGF mRNA was barely detectable in keratinocytes at the ulcer margin and was not visibly increased after treatment [29].
• VEGF and PlGF transcription was assessed by in situ hybridization [29].
• The regulation of the PlGF gene and protein expression by growth factors and cytokines was evaluated by quantitative PCR and ELISA [30].

References