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(Circulation Research. 2005;97:488.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Sarco/Endoplasmic Reticulum Ca²⁺-ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

Larissa Lipskaia, Federica del Monte, Thierry Capiod, Sabrina Yacoubi, Lahouaria Hadri, Michel Hours, Roger J. Hajjar, Anne-Marie Lompré

From the INSERM U621/IFR-14 (L.L., S.Y., L.H., A.-M.L.), UPMC-CHU Pitié-Salpêtrière, Paris, France; the Cardiovascular Research Center (F.d.M., R.J.H.), Massachusetts General Hospital and Harvard Medical School, Charlestown, Mass; INSERM EMI 0228/IFR-118, USTL (T.C.), Villeneuve d’Ascq, France; and the Service de Cytometrie IBAIC (M.H.), IFR-FR46, Université Paris-Sud, Faculté des Sciences, Orsay, France.

Correspondence to Anne-Marie Lompré, INSERM U621, Faculté de Médecine Pitié-Salpétrière, 91 bd de l’Hôpital, 75634 Paris Cedex 13, France. E-mail lompre{at}chups.jussieu.fr

Proliferation of vascular smooth muscle cells (VSMC) is a primary cause of vascular disorders and is associated with major alterations in Ca²⁺ handling supported by loss of the sarco/endoplasmic reticulum calcium ATPase, SERCA2a. To determine the importance of SERCA2a in neointima formation, we have prevented loss of its expression by adenoviral gene transfer in a model of balloon injury of the rat carotid artery. Two weeks after injury, the intima/media ratio was significantly lower in SERCA2a-infected than in injured noninfected or injured ß-galactosidase–infected carotids (0.29±0.04 versus 0.89±0.19 and 0.72±0.14, respectively; P<0.05), and was comparable to that observed in control carotids (0.21±0.03). The pathways leading to proliferation were analyzed in serum-stimulated VSMC. Forced expression of SERCA2a arrested cell cycle at the G1 phase and prevented apoptosis. SERCA2a inhibits proliferation through inactivation of calcineurin (PP2B) and its target transcription factor NFAT (nuclear factor of activated T-cells) resulting in lowering of cyclin D1 and pRb levels. By using NFAT-competing peptide VIVIT, we showed that NFAT activity is strongly required to promote VSMC proliferation. In conclusion, we provide the first evidence that increasing SERCA2a activity inhibits VSMC proliferation and balloon injury–induced neointima formation.

Key Words: vascular smooth muscle cell proliferation • gene transfer • SERCA2a • calcium signaling • nuclear factor of activated T-cells

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