COMPARISON OF NORMAL AND TUMORIGENIC ENDOTHELIAL-CELLS - DIFFERENCES IN THROMBOSPONDIN PRODUCTION AND RESPONSES TO TRANSFORMING GROWTH-FACTOR-BETA

Cultured endothelial cells constitutively synthesize significant level s of thrombospondin, an extracellular matrix-associated protein with r eported anti-angiogenic properties. However, two murine endothelial ce ll lines, bEND.3 and Py-4-1, which have been immortalized with polyoma T oncogenes and which generate vascular malformations in vivo, produc e little or no thrombospondin though bEND.3 (but not Py-4-1) growth is inhibited by the addition of exogenous thrombospondin. In addition, P y-4-1 cells are not growth-inhibited by transforming growth factor-bet a, a potent endothelial inhibitor. These results indicate that these t wo cell lines may be useful tools in understanding the role and mechan ism of action of thrombospondin and transforming growth factor-beta in endothelial cell biology. A role for thrombospondin in vascular devel opment is further suggested by the observation of significant differen ces in the levels of thrombospondin mRNA and protein between capillary and aortic endothelial cells. Transforming growth factor-beta-1 treat ment of normal endothelial cells increases steady-state levels of thro mbospondin mRNA and protein and results in extensive deposition of thr ombospondin into the extracellular matrix. In contrast, transforming g rowth factor-beta-1 has little effect on thrombospondin levels in the tumorigenic endothelial cell lines. In view of our earlier finding tha t contact between endothelial cells and mural cells generates activate d transforming growth factor-beta-1, and the fact that thrombospondin is present in a fibrillar network around vascular structures in vitro, we speculate that modulation of thrombospondin production and distrib ution by transforming growth factor-beta may be a physiological proces s to enjoin stabilization of vessels and cessation of vessel growth.