Cell-cell signalling in capillary stabilisation : implications for therapeutic angiogenesis
Homotypic and heterotypic cell interactions are critical in the assembly and maturation of blood vessels. The aim of this study was to determine the role of Angiopoietin-1 in controlling interaction between endothelial cells and mural cells, and define the classes of molecules involved in mediating this interaction. The influence of heterotypic cell interaction on expression of activin receptor-like kinase 1 (ALK-1) was examined in order to gain insight into the mechanisms of mural cell control of endothelial phenotype. In addition, to begin to explore cell-cell interaction in vessel assembly in vivo attempts were made to establish a non-invasive model for inducing neovessel formation.;Angiopoietin-1 was found to stimulate adhesion between endothelial cells and smooth muscle cells by more than two-fold. This adhesion was calcium-dependent and inclusion RGD-peptides decreased adhesion by 70%, and decreased the effect of Angiopoietin-1 by 66%. Blockade of neural-cadherin (N-cadherin) with cyclic-HAV peptides decreased heterotypic adhesion between endothelial cells and mural cells by 30%. N-cad was found to localise strongly to junctions between smooth muscle cells and homotypic adhesion between these cells was inhibited by inclusion of N-cad-blocking peptides. Previous work suggested ALK-1 expression was modulated by endothelial cell-mural cell contact. No evidence was found for contact-induced changes in expression of ALK-1 under the conditions of this study. An in vivo model for augmenting microvessel number was established in patients with peripheral vascular disease by local application of subcontractile electrical stimulation.;These studies define a direct role for Angiopoietin-1 in control of heterotypic interaction between cells of the vessel wall and show involvement of both integrins and N-cadherin in this interaction. The non-invasive model for increasing neovessel density could be useful for examining capillary stabilisation in vivo in future studies.