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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1204.)
© 2004 American Heart Association, Inc.

Vascular Biology

R-Cadherin:ß-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation

Sadie C. Slater; Evgenia Koutsouki; Christopher L. Jackson; Raymond C. Bush; Gianni D. Angelini; Andrew C. Newby; Sarah J. George

From Bristol Heart Institute, Department of Cardiac, Anesthetic, and Radiological Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, UK.

Correspondence to Dr Sarah Jane George, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, BS2 8HW, UK. E-mail s.j.george{at}bris.ac.uk

Objective— Vascular smooth muscle cell (VSMC) proliferation is an important component of atherosclerosis, restenosis after angioplasty and stent placement, and vein graft failure. Outside-in signaling from the cadherin:ß-catenin complex can increase transcription of the cell-cycle gene cyclin D1; however, its role in VSMC proliferation has only recently been considered.

Methods and Results— We examined the involvement of R-cadherin and ß-catenin in VSMC proliferation in balloon-injured carotid arteries in vivo and aortic rings in vitro. The number of medial VSMCs positive for R-cadherin was significantly reduced by 32%±5%, 52%±10%, and 23%±2% at 0.25, 24, and 48 hours after injury in vivo, respectively. These changes in cadherin expression coincided with the detection of nuclear ß-catenin and elevated cyclin D1 expression. Furthermore, loss of R-cadherin expression was associated with medial VSMC proliferation. Inhibition of classical cadherin function with a HAV peptide and R-cadherin neutralizing antibodies significantly increased proliferation by 4.3±1.0-fold and 4.1±0.98-fold, and increased the number of cells with ß-catenin in the nucleus and expressing cyclin D1 in aortic rings.

Conclusions— These results suggest that R-cadherin expression and ß-catenin signaling may be associated with increased cyclin D1 expression and VSMC proliferation and may therefore play an important role in vascular disease.

Human VSMCs that overexpress AIF-1 grow more rapidly and express G-CSF. G-CSF is capable of promoting VSMC proliferation, and AIF-1-transduced VSMCs are chemotactic for monocytes. This study indicates that AIF-1 enhances VSMC growth by autocrine production of G-CSF, and AIF-1 expression may influence VSMC-inflammatory cell communication.

Key Words: smooth muscle • cadherin • proliferation • intimal thickening

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