|
Neovascularization of the atherosclerotic plaque contributes to local plaque destabilization, internal haemorrhage and rupture leading to such clinical consequences as thrombosis, ischaemic stroke and myocardial infarction. T-cadherin (T-cad) is an atypical GPI-anchored member of the cadherin superfamily of adhesion molecules. T-cad is highly expressed in the cardiovascular system including endothelial cells (EC) from large arteries and veins, capillaries and aortic adventitial vasa vasorum. Its expression level in endothelial and smooth muscle cells is markedly increased during atherosclerosis, restenosis after balloon angioplasty and tumour neovascularization. In vitro, homophilic ligation of T-cad receptors on the EC surface causes cell detachment, induces the motile phenotype and facilitates migration, while overexpression of T-cad in EC increases cell cycle progression and proliferation. Since all these processes are critical steps in angiogenesis, the AIM of the present study was to examine whether T-cad may play a role in control of neovascularization. METHODS AND RESULTS: T-cad influence on angiogenesis was analysed using 2-dimensional model of endothelial differentiation into capillary-like tubular structures (in fixed cells and in living cultures using time-lapse videomicroscopy), spheroid assay in collagen and fibrin 3-dimensional gels, and modified Nicosia mouse heart in vitro assay. Effects of T-cad homophilic ligation with recombinant soluble extracellular domain of T-cad molecule and of T-cad overexpression in cultured EC using adenoviral expression system were studied. We demonstrate that recombinant T-cad protein stimulates formation of tubular structures and arrangement of EC into interconnecting capillary-like networks, the resulting pattern closely resembling the initial response of EC to a pro-angiogenic environment. Overexpression of T-cad stimulates outgrowth of multicellular endothelial sprouts into fibrin and collagen gels. Inclusion of recombinant T-cad protein into 3-dimensional gels increases capillary sprouting both in spheroid and Nicosia assays. We conclude that T-cad is a new stimulator of angiogenesis and suggest that this molecule can contribute to progression of pathological conditions associated with abnormal neovascularization such as tumour angiogenesis or neovascularization of atherosclerotic plaque.
|
J. Vasc. Biol. 42, Sup:2 (2005) pp47-48