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

• Published in: Circulation research Vol. 97; no. 1; pp. 25 - 34
• Main Authors: van der Veer, Eric, Nong, Zengxuan, O’Neil, Caroline, Urquhart, Brad, Freeman, David, Pickering, J Geoffrey
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 08.07.2005; Lippincott
• Subjects: Apoptosis; Biological and medical sciences; Cell Survival; Cells, Cultured; Cytokines - physiology; Fundamental and applied biological sciences. Psychology; Humans; Muscle, Smooth, Vascular - cytology; Myocytes, Smooth Muscle - physiology; NAD - physiology; Neovascularization, Physiologic; Nicotinamide Phosphoribosyltransferase; Oxidation-Reduction; Pentosyltransferases - metabolism; RNA, Small Interfering - pharmacology; Sirtuins - metabolism; Up-Regulation; Vertebrates: cardiovascular system; vascular smooth muscle; Enzyme; Transferases; Glycosyltransferases; Smooth muscle; pre-B-cell colony-enhancing factor; Protein; Vertebrata; maturation; Mammalia; Nicotinamide phosphoribosyltransferase; deacetylation; Circulatory system; Pentosyltransferases
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000173298.38808.27

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.