Research objectives and content The initial phase of tumor development is limited by the absence of vascularization. Anoxic and nutritional stress elicit the production by the tumoral cells of angiogenic factors, such as bFGF and VEGF, that stimulate the proliferation of the endothelial cells from the neighbouring capillaries. Endothelial cells, normally quiescent, carry all the information to form whole capillary networks, but the intracellular signals implicated in the proliferation and differentiation of endothelial cells are not well understood. In this context, our general objective will be identify the intracellular signals which promote either the proliferation or growth arrest of endothelial cells, and the signals implicated in their differentiation. We will focus our attention on the involvement of the MAP kinase cascades in these processes. Endothelial cells undergo growth arrest in response to cellular contact. In epithelial cells such inhibition is due to an upregulation of the p27 cyclin inhibitor. Our current research has revealed that in several different endothelial cell models in culture, activation of MAP kinase in response to mitogens is potently attenuated in confluent cells in comparison with sparse cells. Hence. in the first part of the project our objective will be to study at what level of the MAP kinase cascade the inhibition occurs. The second objective will to asses the importance of an inhibition of the MAP kinase cascade in confluent endothelial cells to the contact mediated growth arrest process. Is an inhibition of MAP kinase directly responsable of the growth arrest in contact inhibited cells? Does this inhibition of MAP kinase lead to the upregulation of the cyclin inhibitor p27 protein levels observed in confluent cells in comparison with sparse cells? The third and last objective of this project will be examine the participation of the three major MAP kinase cascades (MAPK, Jun N-terminal kinase and p38 MAP kinase) and signalling molecules such as phosphatidylinositol 3'-kinase, p70 S6 kinase or nitric oxide, in the differentiation of the endothelial cells, in both in vitro and in vivo models of differentiation. Training content (objective, benefit and expected impact) These studies should allow us to identify the mechanisms by which endothelial cells are growth arrested in vivo together with the identification of the signaling cascades required for the maintenance of the differentiated tube phenotype. The identification of these signals will significantly aid the development of new products that could be useful for inhibiting the uncontrolled growth of endothelial cells that occurs during the pathogenesis of several disease states such as tumour progression, arthritis or diabetic retinopathy.
Links with industry / industrial relevance (22) None