Abstract
Senescent cells may exert detrimental effect on microenvironment through the secretion of soluble factors and the release of extracellular vesicles, such as microparticles, key actors in ageing and cardiovascular diseases. We previously reported that sirtuin-1 (SIRT1) deficiency drives accelerated senescence and dysfunction of endothelial colony-forming cells (ECFC) in PT neonates. Because preterm birth (PT) increases the risk for cardiovascular diseases during neonatal period as well as at adulthood, we hypothesized that SIRT1 deficiency could control the biogenesis of microparticles as part of a senescence–associated secretory phenotype (SASP) of PT-ECFC and investigated the related molecular mechanisms. Compared to control ECFC, PT-ECFC displayed a SASP associated with increased release of endothelial microparticles (EMP), mediating a paracrine induction of senescence in naïve endothelial cells. SIRT1 level inversely correlated with EMP release and drives PT-ECFC vesiculation. Global transcriptomic analysis revealed changes in stress response pathways, specifically the MAPK pathway. We delineate a new epigenetic mechanism by which SIRT1 deficiency regulates MKK6/p38MAPK/Hsp27 pathway to promote EMP biogenesis in senescent ECFC. These findings deepen our understanding of the role of ECFC senescence in the disruption of endothelial homeostasis and provide potential new targets towards the control of cardiovascular risk in individuals born preterm.
Highlights
Senescent cells may exert detrimental effect on microenvironment through the secretion of soluble factors and the release of extracellular vesicles, such as microparticles, key actors in ageing and cardiovascular diseases
In the context of stress-induced premature senescence (SIPS) affecting preterm birth (PT)-endothelial colony-forming cells (ECFC), we show that PT-ECFC develop a senescence–associated secretory phenotype (SASP) characterized by increased levels of inflammatory cytokines and endothelial microparticles (EMP) able to propagate endothelial senescence
This study identifies a new epigenetic mechanism linking the SIRT1 and p38MAPK pathways to control the biogenesis of EMP by senescent ECFC
Summary
Senescent cells may exert detrimental effect on microenvironment through the secretion of soluble factors and the release of extracellular vesicles, such as microparticles, key actors in ageing and cardiovascular diseases. According to the cell type and senescence context text[15], SASP components such as cytokines, proteases, and extracellular vesicles (EV)[16, 17] modulate the behavior of neighboring cells in a paracrine and/or autocrine manner, alter the cellular microenvironment, and can contribute to the functional decline of tissues and the progression of aging-related diseases[18,19,20] This concept is mainly based on in vitro studies of fibroblasts undergoing excessive replication, but to our knowledge no ex vivo studies have characterized endothelial SAPS in the context of SIPS associated to cardiovascular risk factors
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