Atypical GPI-Anchored T-Cadherin Stimulates Angiogenesis In Vitro and In Vivo

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Abstract
Objective— T-cadherin (T-cad) is an atypical GPI-anchored member of the cadherin superfamily. In vascular tissue, T-cad expression is increased during atherosclerosis, restenosis, and tumor neovascularization. In vitro, overexpression and/or homophilic ligation of T-cad on endothelial cells (ECs) facilitates migration, proliferation, and survival. This study investigated T-cad effects on angiogenesis. Methods and Results— In vitro, T-cad homophilic ligation induced arrangement of ECs into a capillary-like network in a 2-dimensional model of EC differentiation and stimulated in-gel endothelial sprout outgrowth in an EC spheroid model and a modified Nicosia tissue assay. Sprouting from spheroids composed of adenoviral-infected T-cad overexpressing ECs or T-cad siRNA transfected ECs were significantly increased or reduced, respectively. In vivo, T-cad potentiated VEGF effects on neovascularization in a model of myoblast-mediated gene transfer to mouse skeletal muscle; vessel caliber after co-delivery of T-ca... This study demonstrates that GPI-anchored T-cadherin stimulates angiogenesis in 2-dimensional model of endothelial differentiation, in 3-dimensional endothelial spheroid, and Nicosia tissue assays in vitro. In vivo, T-cad potentiates VEGF effects on neovascularization in mouse skeletal muscle. We conclude that T-cad is a novel modulator of angiogenesis.