Pre-B-cell colony-enhancing factor regulates NAD+-dependent protein deacetylase activity and promotes vascular smooth muscle cell maturation.
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.
van der Veer
Eric
E
Robarts Research Institute (Vascular Biology Group), Department of Medicine (Cardiology), University of Western Ontario, London, Canada.
Nong
Zengxuan
Z
O'Neil
Caroline
C
Urquhart
Brad
B
Freeman
David
D
Pickering
J Geoffrey
JG
D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009243:NAD / Q000502:physiology*; D018919:Neovascularization, Physiologic; D054409:Nicotinamide Phosphoribosyltransferase; D010084:Oxidation-Reduction; D010430:Pentosyltransferases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D037761:Sirtuins / Q000378:metabolism*; D015854:Up-Regulation
D016207:Cytokines; D034741:RNA, Small Interfering; D009243:NAD; D010430:Pentosyltransferases; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D037761:Sirtuins