Effects Of SU5416 Research Articles

Effects of SU5416 on angiogenesis and the ERK-VEGF/MMP-9 pathway in rat endometriosis.

SU5416 is a small molecule vascular endothelial growth factor (VEGF) receptor signal transduction inhibitor, which can block the VEGF re-ceptor autophosphorylation and inhibit receptor tyrosine kinase signal trans-duction, thereby reducing VEGF activity. However, there are few reports about the correlation of SU5416 to the occurrence and angiogenesis in endometrio-sis. In this study, we observed the effects of VEGF receptor inhibitor SU5416 on angiogenesis in endometriosis in rats. Thirty femalespecific-pathogen-free Sprague-Dawley rats were randomly divided into sham operation group (SOG), model group (MG), and SU5416 group (n=10 for each group). In the SOG, only the uterus was cut and sutured, and endometriosis models were established in the MG and SU5416 group by autologous transplantation. The SU5416 group was injected with 15 mg/kg SU5416 intraperitoneally, and the SOG and MG were intraperitoneally injected with an equal volume of normal saline for 6 weeks. The volume of ectopic lesions was lower in the SU5416 group at 42 d postoperatively thanin the MG (p<0.05). The proportion of CD31-positive cells in the endometrial tissue of the SU5416 group was lower than that of the MG (p<0.05); angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), laminin-5γ2 (LN-5γ2) and phosphorylation of ERK (P-ERK), VEGF, matrix metalloproteinase (MMP)-2, and MMP-9 protein expressions were lower in the SU5416 groupthan in the MG (p<0.05).VEGFreceptor inhibitor SU5416 can inhibit endometrio-sis angiogenesis and reduce inflammatory response in rats, and its mechanism of action may be related to the down-regulation of the ERK-VEGF/MMP-9 path-way expression.

Effects of SU5416 and a vascular endothelial growth factor neutralizing antibody on wear debris-induced inflammatory osteolysis in a mouse model

BackgroundThe development of highly vascularized and inflammatory periprosthetic tissue characterizes the progress of aseptic loosening, a major complication of joint arthroplasty. Vascular endothelial growth factor (VEGF) is an important cell signaling protein involved in angiogenesis. The purpose of this study was to investigate whether R2/Fc (a VEGF neutralizing antibody) and SU5416 (a VEGF receptor II [Flk-1] inhibitor) could ameliorate particle-induced inflammatory osteolysis in a mouse model.MethodsUltrahigh molecular weight polyethylene (UHMWPE) particles were introduced into established air pouches in BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. Drug treatment was started 2 weeks after bone implantation, and mice without drug treatment were included as controls. Pouch tissues were harvested 4 weeks after bone implantation for molecular and histological analysis, and implanted bone degradation was analyzed by microcomputed tomography.ResultsExposure to UHMWPE particles induced inflammatory osteolysis, which was associated with increased expression of VEGF/Flt-1 proteins. Treatment with R2/Fc significantly improved UHMWPE particle-induced inflammatory osteolysis, and reduced the expression of VEGF/Flt-1 proteins. However, SU5416 treatment showed no effect on UHMWPE particle-induced inflammatory osteolysis.ConclusionOur findings indicate that VEGF signaling exerts a regulatory effect on the development of UHMWPE-induced inflammatory osteolysis, through its unique Flt-1, rather than Flk-1, receptor located on monocyte/macrophage cell lineages. These data provide a biological rationale for a VEGF/Flt-1-targeted treatment strategy, especially during the early stages of the wear debris-induced inflammatory response.

Effect of SU5416, an inhibitor of angiogenesis, on processing of the beta-amyloid precursor protein in primary neuronal and astrocytic cells derived from brain tissue of Tg2576 mice

A large number of Alzheimer patients demonstrate cerebrovascular pathology, and functional vascular abnormalities are one of the earlier clinical manifestations in Alzheimer's disease (AD). There are a number of studies providing evidence that the cerebrovascular degenerations in AD are related to β-amyloid (Aβ) deposition. Aβ peptides have been described to inhibit angiogenesis both in vitro and in vivo, and deregulation of angiogenic factors may contribute to various neurological disorders including neurodegeneration. One of the key angiogenic factor is the vascular endothelial growth factor (VEGF). Increased levels of VEGF have been observed in brains of Alzheimer patients, while the functional significance of VEGF up-regulation in the pathogenesis and progression of AD is still a matter of debate. The upregulation of VEGF in response to hypoxic, or ischemic stress, suggests its involvement also in processing of the amyloid precursor protein (APP). To test whether inhibition of angiogenesis may affect APP processing, primary neuronal and astrocytic cells derived from transgenic Tg2576 mice that over express the Swedish mutation of human APP, were exposed by the VEGF receptor antagonist and inhibitor of angiogenesis, SU5416, and the effects of SU5416 on APP metabolism were examined. Exposure of primary neuronal cells by SU5416 for 24 hours resulted in increased release of sAPPβ, and strikingly enhanced secretion of Aβ(1-40) and Aβ(1-42) into the culture medium, which was accompanied by a significant increase in β-secretase activity, as compared to control incubations. In contrast, incubation of primary astrocytes in the presence of SU5416 for 24h resulted in decreased secretion of Aβ(1-40) and Aβ(1-42), and sAPPβ into the culture medium, as compared to control incubations. The SU5416-induced effects on APP processing could not be suppressed by the additional presence of VEGF, sugesting that SU5416 affects pathways that are apparently independent of VEGF receptor signaling. The data obtained indicate that the angiogenesis inhibitor SU5416 may affect APP processing but differentially acting in neurons and astrocytes.The data further suggest a link of angiogenesis and pathogenesis of Alzheimer's disease.