© 1999 American Heart Association, Inc.
Cellular Biology |
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
From the Laboratorio de Nefrología (M.A.C., M.V.A.A., F.R.G.-P., C.C.) and Servicio de Inmunología (E.A., E.T., R.B.), Fundación Jiménez Díaz, Servicio de Anatomía Patológica (P.A.), Hospital Clínico de San Carlos, Autónoma and Complutense Universities, Madrid, Spain.
Correspondence to C. Caramelo, MD, Fundación Jiménez Díaz, Universidad Autónoma, Av Reyes Católicos 2, 28040, Madrid, Spain.
Abstract—The mechanisms involved in the blockade of proliferation in confluent endothelial cells are insufficiently understood. In this regard, the continuity of intercellular junctions appears to be critical to the regulation of endothelial monolayer cell growth. The present study examined the hypothesis that 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, and expression of vascular endothelial growth factor (VEGF) under conditions of disruption of the intercellular junctions between endothelial cells. Disruption of cell junctions was produced by means of a specific anti–vascular endothelial cadherin monoclonal antibody, EGTA, or cytochalasin D. Our results disclosed that these maneuvers induce an increase in VEGF mRNA production, with transcription of the 121–, 165–, and 189–amino acid isoforms of VEGF. Further evidence of the relationship between endothelial cells monolayer 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 cytoprotective effects, as assessed by [3H]thymidine uptake, 51Cr release, and flow cytometry. In conclusion, our results reveal that disruption of homophilic interendothelial junctions induces VEGF expression. Under these conditions, autocrine VEGF appears to have a relevant role in death inhibition and proliferation of endothelial cells.
Key Words: vascular endothelial growth factor • vascular endothelial cadherin • endothelial cell • cytoprotection • proliferation
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