T-cadherin upregulation correlates with cell-cycle progression and promotes proliferation of vascular cells

Objective: In vascular tissue, T-cadherin (T-cad) levels correlate with the progression of atherosclerosis, restenosis and tumour neovascularization. This study investigates whether T-cad influences proliferation of vascular cells. Methods and Results: Cultures of human umbilical vein endothelial cells (HUVEC) and rat and human aortic smooth muscle cells (rSMC, hSMC) were used. T-cad was overexpressed in HUVEC and hSMC using an adenoviral expression system. In cultures released from G1/G0 synchrony parallel immunoblot analysis of T-cad and cell cycle phase specific markers (p27Kip1, cyclin D1, E2F1, PCNA, cyclin B) showed increased T-cad protein levels subsequent to entry into early S-phase with sustained elevation through S-and M-phases. T-cad was increased in G2/M-phase (colchicine) synchronized cultures. In FACS-sorted cell populations, expression of T-cad in S-and G2/M-phase was higher than G1/G0-phase. Compared with empty-and LacZ-vector infected controls, HUVEC and hSMC overexpressing T-cad exhibited increased proliferation as assessed in enumeration and DNA synthesis assays. Additionally, following release from G1/G0 synchrony, HUVEC and hSMC overexpressing T-cad enter S-phase more rapidly. Flow cytometry after BrdU/propidium labelling confirmed increased cell cycle progression in T-cad overexpressing cells. Conclusion: In vascular cells, T-cad is dynamically regulated during the cell cycle and its expression functions in the promotion of proliferation. T-cad may facilitate progression of proliferative vascular disorders such as atherosclerosis, restenosis and tumour angiogenesi