Disruption of cadherin-related junctions triggers autocrine expression of vascular endothelial growth factor in bovine aortic endothelial cells - Effects on cell proliferation and death resistance

The mechanisms involved in the blockade of proliferation in confluent endot helial cells are insufficiently understood. In this regard, the continuity of intercellular junctions appears to be critical to the regulation of endo thelial monolayer cell growth. The present study examined the hypothesis th at the disruption of the intercellular adherens junctions will trigger both endothelial cell proliferation and autocrine production of growth factors. With this purpose, we assessed the changes in growth, death resistance, an d expression of vascular endothelial growth factor (VEGF) under conditions of disruption of the intercellular junctions between endothelial cells. Dis ruption of cell junctions was produced by means of a specific anti-vascular endothelial cadherin monoclonal antibody, EGTA, or cytochalasin D. Our res ults disclosed that these maneuvers induce an increase in VEGF mRNA product ion, with transcription of the 121-, 165-, and 189-amino acid isoforms of V EGF. Further evidence of the relationship between endothelial cells monolay er continuity and VEGF protein expression was obtained by the demonstration of an increase in VEGF protein, as determined by Western blot, induced by the aforementioned maneuvers, as well as by immunocytochemical detection of increased VEGF staining in the areas surrounding a mechanical endothelial injury and in endothelial cells at subconfluence. In functional terms, the autocrine expression of VEGF was associated with growth-promoting and cytop rotective effects, as assessed by [H-3]thymidine uptake, Cr-51 release, and now cytometry. In conclusion, our results reveal that disruption of homoph ilic interendothelial junctions induces VEGF expression. Under these condit ions, autocrine VEGF appears to have a relevant role in death inhibition an d proliferation of endothelial cells.