Alteration of E2F2 Expression in Governing Endothelial Cell Senescence

Abstract

Endothelial cell senescence has a vital implication for vascular dysfunction, leading to age-related cardiovascular disease, especially hypertension and atherosclerosis. E2F transcription factor 2 (E2F2) plays a critical role in cell proliferation, differentiation, and DNA damage response. Up to date, no study has ever connected E2F2 to vascular endothelial cell senescence. Here, we demonstrate that E2F2 is involved in endothelial cellular senescence. We found that E2F2 expression is decreased during the replicative senescence of human umbilical vein endothelial cells (HUVECs) and the aortas of aged mice. The knockdown of E2F2 in young HUVECs induces premature senescence characterized by an increase in senescence-associated β-galactosidase (SA-β-gal) activity, a reduction in phosphorylated endothelial nitric oxide synthase (p-eNOS) and sirtuin 1 (SIRT1), and the upregulation of senescence-associated secretory phenotype (SASP) IL-6 and IL-8. The lack of E2F2 promoted cell cycle arrest, DNA damage, and cell proliferation inhibition. Conversely, E2F2 overexpression reversed the senescence phenotype and enhanced the cellular function in the senescent cells. Furthermore, E2F2 deficiency downregulated downstream target genes including CNNA2, CDK1, and FOXM1, and overexpression restored the expression of these genes. Our findings demonstrate that E2F2 plays an indispensable role in endothelial cell senescence.

Endothelial Senescence in Neurological Diseases

“…In addition, senescence-associated β-galactosidase (SA-β-gal) accumulates in lysosomes [ 1 ], and when the β-gal substrate X-gal is provided to the cells, senescent cells activate the substrate and turn it dark blue, allowing the senescent cells to be observed by ordinary functional microscopy. Detection of SA-β-gal activity by Liu [ 38 ] and Le [ 39 ] et al confirmed the presence of senescent ECs. Although SA-β-gal is evident in senescent cells, there is an argument that it is neither necessary nor a determinant of the senescence phenotype [ 1 ].…”

Biomarkers of Aging and Relevant Evaluation Techniques: A Comprehensive Review

“…In aged mice, p16 and p21 aggregate greater in hippocampal microglia, oligodendrocyte progenitor cells, and oligodendrocytes with some degree of heterogeneity [ 212 ]. The mouse senescent cell atlas, completed in 2020, contains sequencing data from 23 mouse tissues collected throughout their lifespan and demonstrates that p16, E2f2, Lmnb1, Tnf, and Itgax expression increases considerably with aging [ 213 ]; however, E2f2 is typically downregulated in senescent cells [ 214 ]. Another study compared transcriptome differences in the spleen, kidney, and lungs of aging and young mice using single-cell sequencing and discovered that different cell types display different aging trajectories as a consequence of gene enrichment [ 215 ].…”

A potential role of autophagy-mediated vascular senescence in the pathophysiology of HFpEF

“…Additionally, alterations in mitochondrial biogenesis ( 107 ), NFkB activation ( 108 ), increased matrix metalloproteinase (MMP) secretion ( 109 ) and reduced eNOS activity ( 110 ) have also been described. In human umbilical vein ECs (HUVECs), knockdown of the transcription factor E2F2 induced senescence in these cells and its overexpression decreased senescence markers; interestingly, a lower expression of E2F2 was seen in aortas of aged mice ( 111 ). These experiments suggest that E2F2 can be a potential target to modulate senescence in vivo , yet its participation in HFpEF remains unknown.…”