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      Microvasculature Change and Placenta Growth Factor Expression in the Early Stage of a Rat Remnant Kidney Model

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          Background/Aim: There is significant loss of microvasculature and impaired angiogenesis in rat remnant kidney (RK). Placenta growth factor (PlGF) is a potential angiogenic growth factor. In this study, we investigate the changes of microvasculature and expression of PlGF in the first 4 weeks of the early stage of a rat RK model. Method: RK was induced by right nephrectomy and ligation of two of the three branches of the left renal arteries (equivalent to 5/6 subtotal nephrectomy). Blood urea nitrogen (BUN), serum creatinine (Scr), and blood pressure (BP) were measured. Proliferation of endothelial cells was identified by double staining of two antibodies, anti-rat endothelial cell (RECA-1) and antiproliferating cell nuclear antigen (PCNA). RT-PCR and Western blot were used for PlGF analysis. Results: BUN, Scr and BP remained stable after rising within the first week. An angiogenic response occurred in RKs, with an increase in the proliferation of peritubular and glomerular endothelial cells. Both PlGF protein and mRNA expression were significantly upregulated 2- to 3-fold in RK at week 1 and week 2, compared to the sham-operated group (p < 0.05). Conclusion: The expression of PlGF is upregulated and coincident with an early angiogenic response in rat RK, suggesting that PlGF may be involved in angiogenesis in progressive renal injury.

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          Most cited references 9

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          Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1.

          Therapeutic angiogenesis is likely to require the administration of factors that complement each other. Activation of the receptor tyrosine kinase (RTK) Flk1 by vascular endothelial growth factor (VEGF) is crucial, but molecular interactions of other factors with VEGF and Flk1 have been studied to a limited extent. Here we report that placental growth factor (PGF, also known as PlGF) regulates inter- and intramolecular cross talk between the VEGF RTKs 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. 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.
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            VEGFR-1-selective VEGF homologue PlGF is arteriogenic: evidence for a monocyte-mediated mechanism.

            Two signaling receptors for vascular endothelial growth factor (VEGF) in the vasculature are known with not yet well-understood roles in collateral vessel growth (arteriogenesis). In this study, we examined the involvement of the two VEGF receptors in arteriogenesis. Therefore, we used the VEGF homologue placenta growth factor (PlGF), which only binds to VEGFR-1 and VEGF-E, which only recognizes VEGFR-2. These peptides were locally infused over 7 days after ligation of the femoral artery in the rabbit. Evaluation of collateral growth by determining collateral conductance and angiographic scores demonstrated that the VEGFR-1-specific PlGF contributed significantly more to arteriogenesis than the VEGFR-2 specific VEGF-E. The combination of VEGF-E and PlGF did not exceed the effect of PlGF alone, indicating that cooperation of the two VEGF receptors in endothelial cell signaling is not required for arteriogenesis. In an in vitro model of angiogenesis, VEGF and VEGF-E were comparably active, whereas PlGF displayed no activity when given alone and did not further increase the effects of VEGF or VEGF-E. However, PlGF was as potent as VEGF when monocyte activation was assessed by monitoring integrin surface expression. In addition, accumulation of activated monocytes/macrophages in the periphery of collateral vessels in PlGF-treated animals was observed. Furthermore, in monocyte-depleted animals, the ability of PlGF to enhance collateral growth in the rabbit model and to rescue impaired arteriogenesis in PlGF gene-deficient mice was abrogated. Together, these data indicate that the arteriogenic activity observed with the VEGFR-1-specific PlGF is caused by its monocyte-activating properties.
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              In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor.

               J Folkman,  D Shima,  Y Cao (1996)
              To investigate the in vivo angiogenic activity of placenta growth factor (PIGF) and its heterodimers with vascular endothelial growth factor (VEGF), the induction of neovascularization of these factors in the mouse cornea was studied. VEGF165 is sufficiently potent to stimulate new capillary growth from the limbal vessels. PIGF129/VEGF165 heterodimers also induce corneal neovascularization with a maximal vessel length similar to VEGF165, but with a marked decrease of vessel density. In contrast, PIGF129 has little or no effect in this in vivo angiogenesis assay. The expression of VEGF mRNA and protein is drastically up-regulated by hypoxia in choriocarcinoma cells, whereas expression of PIGF is not affected by the low concentration of oxygen. Up-regulation of VEGF production results in increased formation of PIGF/VEGF heterodimers in these tumor cells. Thus, hypoxia indirectly up-regulates expression levels of PIGF/VEGF heterodimers and modulates VEGF activity when these factors are co-expressed.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                April 2006
                05 April 2006
                : 26
                : 1
                : 97-104
                aDepartment of Nephrology, First Affiliated Hospital, and bDepartment of Pathology, Sun Yat-sen University, Guangzhou; cDepartment of Nephrology, Second Affiliated Hospital, School of Medicine, ZheJiang University, Hangzhou, China
                92032 Am J Nephrol 2006;26:97–104
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 6, Tables: 1, References: 26, Pages: 8
                Self URI (application/pdf):
                Original Report: Laboratory Investigation

                Cardiovascular Medicine, Nephrology

                Angiogenesis, Chronic renal injury, Placenta growth factor


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