During our previous work we cloned a new protein selectively expressed by the endothelium of any type of vessels. For this molecule which belongs to the cadherin family of adhesive receptors we proposed the name of VE (vascular endothelial) -cadherin, due to its tissue type-specificity. VE-cadherin presents a cellular localization restricted to the regions of cell to cell contacts. It is known that cadherins are important regulators of morphogenesis, in particular in the embryo. Therefore we asked whether VE-cadherin could play a role in vascular morphogenesis and specifically in the formation of new vessels induced by tumors. In particular we want to verify whether VE-cadherin can transmit messages which inhibit the growth of endothelial cells. The endothelium after reaching confluence loses the ability to respond to growth factors and to proliferate. VE-cadherin, selectively localized at intercellular junctions, is a candidate to control cell contact-induced growth inhibition in the endothelium. In this context it is worth recalling that the expression of cadherins in tumor cells is inversely related to their invasive ability. We will verify this activity of VE-cadherin using tools which are in the majority already available in our laboratory: a) human and murine endothelial cells, b) cells transfected with native or different mutated forms of VE-cadherin, c) antibodies to and recombinant fragments of different regions of VE-cadherin.

It is known that the adhesive activity of the 'transmembrane receptors' cadherins is modulated by their association to cytoplasmic regulatory proteins: the catenins. With the aim to identify the molecular mechanisms through which VE-cadherin can induce inhibition of endothelial proliferation we will analyze the composition of the complex VE-cadherin/catenins and the qualitative modifications of its components (tyrosine phosphorylation) in different stages of cell growth. We will use the cell types and the various reagents indicated previously.

To analyze in in vivo experimental models the role of VE-cadherin in tumor angiogenesis we will produce transgenic animals either with a null mutation of VE-cadherin gene or expressing different mutated form of VE-cadherin via 'plug and socket' gene targeting.