Atypical GPI-anchored T-cadherin stimulates angiogenesis in vitro and in vivo.
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.


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-cad and VEGF was significantly greater than after delivery of VEGF alone.


CONCLUSIONS
We unequivocally identify T-cad as a novel modulator of angiogenesis and suggest that this molecule can be exploited as a target for modulation of therapeutic angiogenesis, as well as for prevention of pathological conditions associated with abnormal neovascularization.
Philippova
Maria
M
Cardiovascular Signalling Group, Basel University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland. maria.filippova@unibas.ch
Banfi
Andrea
A
Ivanov
Danila
D
Gianni-Barrera
Roberto
R
Allenspach
Roy
R
Erne
Paul
P
Resink
Thérèse
T
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004730:Endothelium, Vascular / Q000254:growth & development; D018014:Gene Transfer Techniques; D017261:Glycosylphosphatidylinositols / Q000502:physiology*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D018874:Spheroids, Cellular; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D043925:Angiogenesis Inducing Agents; D015820:Cadherins; D017261:Glycosylphosphatidylinositols; C099972:H-cadherin; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A