Cell adhesion molecule T-cadherin regulates vascular cell adhesion, phenotype and motility Danila Ivanov, a Maria Philippova, a, * Vsevolod Tkachuk, b Paul Erne, c and The ´re `se Resink a a Cardiovascular Laboratories, Department of Research, Basel University Hospital, CH 4031 Basel, Switzerland b Laboratory for Molecular Endocrinology, Institute for Experimental Cardiology, Russian Cardiology Research Center, 121552 Moscow, Russia c Division of Cardiology, Luzern Kantonsspital, CH 6000 Lucerne, Switzerland Received 10 December 2002, revised version received 24 September 2003 Abstract T-cadherin (T-cad), an unusual glycosylphosphatidylinositol (GPI)-anchored member of the cadherin family of cell adhesion molecules, is widely expressed in the cardiovascular system. The expression profile of T-cad within diseased (atherosclerotic and restenotic) vessels indicates some relationship between expression of T-cad and the phenotypic status of resident cells. Using cultures of human aortic smooth muscle cells (SMC) and human umbilical vein endothelial cells (HUVEC) we investigate the hypothesis that T-cad may function in modulating adhesive properties of vascular cells. Coating of culture plates with recombinant T-cad protein or with antibody against the first amino-terminal domain of T-cad (anti-EC1) significantly decreased adhesion and spreading of SMC and HUVEC. HUVECs adherent on T- cad or anti-EC1 substratum exhibited an elongated morphology and associated redistribution of the cytoskeleton and focal adhesions to a distinctly peripheral location. These changes are characteristic of the less-adhesive, motile or pro-migratory, pro-angiogenic phenotype. Boyden chamber migration assay demonstrated that the deadhesion induced by T-cad facilitates cell migration towards a serum gradient. Overexpression of T-cad in vascular cells using adenoviral vectors does not influence cell adhesion or motility per se, but increases the detachment and migratory responses induced by T-cad substratum. The data suggest that T-cad acts as an anti-adhesive signal for vascular cells, thus modulating vascular cell phenotype and migration properties. D 2003 Elsevier Inc. All rights reserved. Keywords: T-cadherin; Cell adhesion; Phenotype Introduction The functional behaviour of vascular cells is highly dependent on their adhesive interactions with each other and their environment. Cell adhesion molecules play a key role in the establishment of homotypic and hetero- typic cell–cell contacts as well as in cell attachment to the extracellular matrix. Different types of cell adhesion molecules have been shown to participate in the mainte- nance of normal vascular tissue architecture and in pathological tissue remodelling during atherosclerosis, restenosis after coronary angioplasty and angiogenesis. These include selectins, which mediate platelet – leukocyte and leukocyte – endothelial cell interactions [1], immuno- globulin family molecules such as VCAM-1, ICAM and PECAM, which are important for adhesion and transmi- gration of blood leukocytes [2], and extracellular matrix receptor integrins, which are involved in platelet adhesion and aggregation as well as in adhesion and migration of smooth muscle and endothelial cells [1]. The participation of another family of cell adhesion molecules, the cadherins, in the formation of blood vessels and maintenance of their structural integrity has been acknowledged only recently. Cadherins are trans- membrane glycoproteins that mediate calcium-dependent homophilic cell–cell adhesion and participate in the establishment of cell polarity, cell sorting and morpho- genesis during embryonic development [3–5]. In the adult organism, loss of cadherin expression and function results in impaired intercellular adhesion, abnormal cell migration 0014-4827/$ - see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.yexcr.2003.09.030 * Corresponding author. Cardiovascular Laboratories, Department of Research, Basel University Hospital, ZLF 320, Hebelstrasse 20, CH 4031 Basel, Switzerland. Fax: +41-61-265-2350. E-mail address: Maria.Filippova@unibas.ch (M. Philippova). www.elsevier.com/locate/yexcr Experimental Cell Research 293 (2004) 207 – 218