title: Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression.
abstract: Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic activity of endothelial colony-forming cells (ECFCs) in this condition. We hypothesized that ECFC dysfunction in PT might result from premature senescence and investigated the underlying mechanisms. Compared with ECFCs from term neonates (n = 18), ECFCs isolated from PT (n = 29) display an accelerated senescence sustained by growth arrest and increased senescence-associated β-galactosidase activity. Increased p16(INK4a) expression, in the absence of telomere shortening, indicates that premature PT-ECFC aging results from stress-induced senescence. SIRT1 level, a nicotinamide adenine dinucleotide-dependent deacetylase with anti-aging activities, is dramatically decreased in PT-ECFCs and correlated with gestational age. SIRT1 deficiency is subsequent to epigenetic silencing of its promoter. Transient SIRT1 overexpression or chemical induction by resveratrol treatment reverses senescence phenotype, and rescues in vitro PT-ECFC angiogenic defect in a SIRT1-dependent manner. SIRT1 overexpression also restores PT-ECFC capacity for neovessel formation in vivo. We thus demonstrate that decreased expression of SIRT1 drives accelerated senescence of PT-ECFCs, and acts as a critical determinant of the PT-ECFC angiogenic defect. These findings lay new grounds for understanding the increased cardiovascular risk in individuals born prematurely and open perspectives for therapeutic strategy.
authors: Aix-Marseille Université, INSERM, Vascular Research Center of Marseille, Unité Mixte de Recherche en Santé 1076, Marseille, France;
authors: Paula Frizera
authors: PF
authors: Vassallo
authors: Stéphanie
authors: S
authors: Simoncini
authors: Isabelle
authors: I
authors: Ligi
authors: Anne-Line
authors: AL
authors: Chateau
authors: Richard
authors: R
authors: Bachelier
authors: Stéphane
authors: S
authors: Robert
authors: Julia
authors: J
authors: Morere
authors: Samantha
authors: S
authors: Fernandez
authors: Benjamin
authors: B
authors: Guillet
authors: Maxime
authors: M
authors: Marcelli
authors: Edwige
authors: E
authors: Tellier
authors: Alain
authors: A
authors: Pascal
authors: Umberto
authors: U
authors: Simeoni
authors: Francine
authors: F
authors: Anfosso
authors: Frédérique
authors: F
authors: Magdinier
authors: Françoise
authors: F
authors: Dignat-George
authors: Florence
authors: F
authors: Sabatier
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000097:blood*; D047928:Premature Birth / Q000097:blood; D056564:Sirtuin 1 / Q000235:genetics*; D013312:Stress, Physiological / Q000502:physiology
chemical_list: C447939:SIRT1 protein, human; D056564:Sirtuin 1