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1 Nephrology-Hypertension, Fundacion Jimenez Diaz, Madrid, Spain; Instituto Reina Sofia de Investigaciones Nefrologicas, Madrid, Spain
2 Nephrology-Hypertension, Fundacion Jimenez Diaz, Madrid, Spain
3 Molecular and Cell Biology, Imclone Systems, New York, NY, USA
4 Nephrology-Hypertension, Fundacion Jimenez Diaz, Madrid, Spain; Medicine, Universidad Autonoma, Madrid, Spain; Instituto Reina Sofia de Investigaciones Nefrologicas, Madrid, Spain
* To whom correspondence should be addressed. E-mail: ccaramelo{at}fjd.es.
Pro-angiogenic, proliferative effects of tumors have been extensively characterized in subconfluent endothelial cells, but results are critically lacking on confluent, contact-inhibited endothelial cells. The present study examined the effect of tumor-conditioned media (CM) of the malignant osteoblastic cell line, MG63-CM, on monolayer, quiescent bovine aorta endothelial cells (EC). MG63-CM and MG63-CM/CoCl2 significantly increased EC survival in serum-starved conditions, without inducing EC proliferation. Furthermore, MG63-CM and MG63-CM/CoCl2, both containing high amounts of vascular endothelial growth factor (VEGF), induced relevant phenotypic changes in EC (all p<0.01) involving increase of nucleoli/chromatin condensations, nucleus/cytosol ratio, capillary-like vacuolated structures, vessel-like, acellular areas, migration through Matrigel, growth advantage in re-seeding and factor VIII. All these actions were significantly inhibited by VEGF and VEGFR2 blockade. Of particular importance, a set of similar effects were detected in a human microvascular endothelial cell line (HMEC). With regards to gene expression, incubation with MG63-CM abolished endogenous VEGF mRNA and protein, but induced a clear-cut increase in VEGFR2 mRNA expression in EC. In terms of mechanism, MG63-CM activates protein kinase B (PKB)/Akt (Akt), p44/p42-mitogen activated protein kinase (MAPK)-mediated pathways, as suggested by both inhibition and phosphorylation experiments. In conclusion, tumor cells activate confluent, quiescent EC, promoting survival, phenotypic and gene expression changes. Of importance, VEGF antagonism converts MG63-CM from protective into EC damaging effects.
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