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(Circulation Research. 2005;97:25.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Pre–B-Cell Colony–Enhancing Factor Regulates NAD⁺-Dependent Protein Deacetylase Activity and Promotes Vascular Smooth Muscle Cell Maturation

Eric van der Veer, Zengxuan Nong, Caroline O’Neil, Brad Urquhart, David Freeman, J. Geoffrey Pickering

From the Robarts Research Institute (Vascular Biology Group) (E.v.d.V., Z.N., C.O., J.G.P.) and London Health Sciences Centre (B.U., D.F., J.G.P.), Departments of Medicine (Cardiology), Biochemistry, Medical Biophysics, Physiology, and Pharmacology, University of Western Ontario, London, Canada.

Correspondence to Dr J. Geoffrey Pickering, London Health Sciences Centre, 339 Windermere Rd, London, Ontario N6A 5A5, Canada. E-mail gpickering{at}robarts.ca

Conversion of vascular smooth muscle cells (SMCs) from a proliferative state to a nonproliferative, contractile state confers vasomotor function to developing and remodeling blood vessels. Using a maturation-competent human SMC line, we determined that this shift in phenotype was accompanied by upregulation of pre–B-cell colony–enhancing factor (PBEF), a protein proposed to be a cytokine. Knockdown of endogenous PBEF increased SMC apoptosis and reduced the capacity of synthetic SMCs to mature to a contractile state. In keeping with these findings, human SMCs transduced with the PBEF gene had enhanced survival, an elongated bipolar morphology, and increased levels of h-caldesmon, smoothelin-A, smoothelin-B, and metavinculin. Notwithstanding some prior reports, PBEF did not have attributes of a cytokine but instead imparted the cell with increased nicotinamide phosphoribosyltransferase activity. Intracellular nicotinamide adenine dinucleotide (NAD⁺) content was increased in PBEF-overexpressing SMCs and decreased in PBEF-knockdown SMCs. Furthermore, NAD⁺-dependent protein deacetylase activity was found to be essential for SMC maturation and was increased by PBEF. Xenotransplantation of human SMCs into immunodeficient mice revealed an increased capacity for PBEF-overexpressing SMCs to mature and intimately invest nascent endothelial channels. This microvessel chimerism and maturation process was perturbed when SMC PBEF expression was lowered. These findings identify PBEF as a regulator of NAD⁺-dependent reactions in SMCs, reactions that promote, among other potential processes, the acquisition of a mature SMC phenotype.

Key Words: vascular smooth muscle • pre–B-cell colony–enhancing factor • maturation • nicotinamide phosphoribosyltransferase • deacetylation

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