TAILIEUCHUNG - Báo cáo khoa học: Platelet factor 4 disrupts the intracellular signalling cascade induced by vascular endothelial growth factor by both KDR dependent and independent mechanisms

The mechanism by which the CXC chemokine platelet fac-tor 4 (PF-4) inhibits endothelial cell proliferation is unclear. The heparin-binding domains of PF-4 have been reported to prevent vascular endothelial growth factor 165 (VEGF165 ) andfibroblast growth factor 2 (FGF2) frominteractingwith their receptors. However, other studies have suggested that PF-4 acts via heparin-binding independent interactions. Here, we compared the effects of PF-4 on the signalling events involved in the proliferation induced by VEGF165 , which binds heparin, and by VEGF121 , which does not | Eur. J. Biochem. 271 3310-3318 2004 FEBS 2004 doi Platelet factor 4 disrupts the intracellular signalling cascade induced by vascular endothelial growth factor by both KDR dependent and independent mechanisms Eric Sulpice1 Jean-Olivier Confreres1 Julie Lacour1 Marijke Bryckaert2 and Gerard Tobelem1 1Institut des Vaisseaux et du Sang Paris 2INSERM U348 Paris France The mechanism by which the CXC chemokine platelet factor 4 PF-4 inhibits endothelial cell proliferation is unclear. The heparin-binding domains of PF-4 have been reported to prevent vascular endothelial growth factor 165 VEGF165 and fibroblast growth factor 2 FGF2 from interacting with their receptors. However other studies have suggested that PF-4 acts via heparin-binding independent interactions. Here we compared the effects of PF-4 on the signalling events involved in the proliferation induced by VEGF165 which binds heparin and by VEGF121 which does not. Activation of the VEGF receptor KDR and phospholipase Cy PLCy was unaffected in conditions in which PF-4 inhibited VEGF121-induced DNA synthesis. In contrast VEGF165-induced phosphorylation of KDR and PLCy was partially inhibited by PF-4. These observations are consistent with PF-4 affecting the binding of VEGF165 but not that of VEGF121 to KDR. PF-4 also strongly inhibited the VEGF165- and VEGF 121-induced mitogen-activated protein MAP kinase signalling pathways comprising Raf1 MEK1 2 and ERK1 2 for VEGF165 it interacts directly or upstream from Raf1 for VEGF121 it acts downstream from PLCy. Finally the mechanism by which PF-4 may inhibit the endothelial cell proliferation induced by both VEGF121 and VEGF165 involving disruption of the MAP kinase signalling pathway downstream from KDR did not seem to involve CXCR3B activation. Keywords CXCR3B KDR MAP kinase PF-4 VEGF. Angiogenesis the formation of new capillary blood vessels is controlled by positive and negative regulators. Tumours secrete potent angiogenic factors .

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