Endothelial cell senescence contributes to pathological retinal angiogenesis

Abstract

Background: Pathological retinal neovascularization is marked by microvas-cular lesions manifested initially as endothelial cell dysfunction and metabolic disturbances. However, the regulatory mechanism guiding retinal vascular endothelial cell function remian controversial.

Main body: Previous studies have demonstarted that high glucose or oxidative stress can induce premature senescence in endothelial cells, triggering inflammatory responses within the vascular system and promoting the secretion of pro-inflammatory factors, ultimately leading to pathological angiogenesis. Endothelial cell senescence has thus become a key target for anti-angiogenic therapies.

Conclusion: This review delves into current research on the mechanisms driving senescence-induced retinal angiogenesis and highlights potential target protein pathways, aiming to provide insights for future investigations.

Keywords

angiogenesis / endothelial cell senescence / retinal neovascularization / retinopathy

References

[1] CampbellM, DoyleSL. Current perspectives on established and novel therapies for pathological neovascularization in retinal disease. Biochem Pharmacol. 2019;164:321-325.

[2] Fevereiro-MartinsM, Marques-Neves C, GuimarãesH, BichoM. Retinopathy of prematurity: a review of pathophysiology and signaling pathways. Surv Ophthalmol. 2023;68:175-210.

[3] TianY, ZhangF, QiuY, et al. Reduction of choroidal neovascularization via cleavable VEGF antibodies conjugated to exosomes derived from regulatory T cells. Nat Biomed Eng. 2021;5:968-982.

[4] ArrigoA, Aragona E, BandelloF. VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy. Ann Med. 2022;54:1089-1111.

[5] XiaoX, XuM, YuH, et al. Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src. Signal Transduct Target Ther. 2021;6:354.

[6] FuZ, SmithLEH. Cellular senescence in pathologic retinal angiogenesis. Trends Endocrinol Metab. 2021;32:415-416.

[7] ChenMS, LeeRT, GarbernJC. Senescence mechanisms and targets in the heart. Cardiovasc Res. 2022;118:1173-1187.

[8] BuL-L, YuanHH, XieLL, Guo MH, LiaoD-F, ZhengXL. New dawn for atherosclerosis: vascular endothelial cell senescence and death. Int J Mol Sci. 2023;24:15160.

[9] GogirajuR, XuX, BochenekML, et al. Endothelial p53 deletion improves angiogenesis and prevents cardiac fibrosis and heart failure induced by pressure overload in mice. J Am Heart Assoc. 2015;4.

[10] Crespo-GarciaS, Tsuruda PR, DejdaA, et al. Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition. Cell Metab. 2021;33:818-832.

[11] ZhaoZ, DongQ, LiuX, et al. Dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest. Genomics. 2020;112:1309-1317.

[12] BloomSI, LiuY, TuckerJR, et al. Endothelial cell telomere dysfunction induces senescence and results in vascular and metabolic impairments. Aging Cell. 2023;22:e13875.

[13] von KobbeC. Cellular senescence: a view throughout organismal life. Cell Mol Life Sci. 2018;75:3553-3567.

[14] SikoraE, ArendtT, BennettM, Narita M. Impact of cellular senescence signature on ageing research. Ageing Res Rev. 2011;10:146-152.

[15] StorerM, MasA, Robert-MorenoA, et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell. 2013;155:1119-1130.

[16] CampisiJ, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729-740.

[17] StabenowLK, et al. Oxidative glucose metabolism promotes senescence in vascular endothelial cells. Cells. 2022;11:2213.

[18] BloomSI, IslamMT, LesniewskiLA, DonatoAJ. Mechanisms and consequences of endothelial cell senescence. Nat Rev Cardiol. 2023;20:38-51.

[19] YinK, PattenDA, GoughS, et al. Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance. Genes Dev. 2022;36:533-549.

[20] MosteiroL, Pantoja C, AlcazarN, et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science. 2016;354:aaf4445.

[21] RohlenovaK, GoveiaJ, García-CaballeroM, et al. Single-cell RNA sequencing maps endothelial metabolic plasticity in pathological angiogenesis. Cell Metab. 2020;31:862-877.

[22] BertelliPM, Pedrini E, HughesD, et al. Long term high glucose exposure induces premature senescence in retinal endothelial cells. Front Physiol. 2022;13:929118.

[23] TeraoR, AhmedT, SuzumuraA, Terasaki H. Oxidative stress-induced cellular senescence in aging retina and age-related macular degeneration. Antioxidants. 2022;11:2189.

[24] LeeKS, LinS, CoplandDA, Dick AD, LiuJ. Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration. J Neuroinflammation. 2021;18:32.

[25] CaiY, et al. Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell Res. 2020;30:574-589.

[26] AvramovicD, Archaimbault SA, KembleAM, GruenerS, Lazendic M, WestenskowPD. TGFβ1 induces senescence and attenuated VEGF production in retinal pericytes. Biomedicines. 2022;10:1404.

[27] ZhouH, LiX, RanaM, Cornelius JF, KhanD, SajjadMN. mTOR inhibitor Rapalink-1 prevents ethanol-induced senescence in endothelial cells. Cells. 2023;12:2609.

[28] YiY-Y, ChenH, ZhangS-B, Xu H-W, FangX-Y, WangS-J. Exogenous Klotho ameliorates extracellular matrix degradation and angiogenesis in intervertebral disc degeneration via inhibition of the Rac1/PAK1/MMP-2 signaling axis. Mech Ageing Dev. 2022;207:111715.

[29] JarrettSG, LinH, GodleyBF, Boulton ME. Mitochondrial DNA damage and its potential role in retinal degeneration. Prog Retin Eye Res. 2008;27:596-607.

[30] HoffmanJM, Robinson R, GreenwayG, et al. Blockade of interleukin-6 trans-signaling prevents mitochondrial dysfunction and cellular senescence in retinal endothelial cells. Exp Eye Res. 2023;237:109721.

[31] LinM-M, LiuN, QinZ-H, Wang Y. Mitochondrial-derived damage-associated molecular patterns amplify neuroinflammation in neurodegenerative diseases. Acta Pharmacol Sin. 2022;43:2439-2447.

[32] SunD, ChenS, LiS, et al. Enhancement of glycolysis-dependent DNA repair regulated by FOXO1 knockdown via PFKFB3 attenuates hyperglycemia-induced endothelial oxidative stress injury. Redox Biol. 2023;59:102589.

[33] MalikAI, StoreyKB. Transcriptional regulation of antioxidant enzymes by FoxO1 under dehydration stress. Gene. 2011;485:114-119.

[34] KimME, KimDH, LeeJS. Transcription factors as targets of natural compounds in age-related diseases and cancer: potential therapeutic applications. Int J Mol Sci. 2022;23.

[35] WangT, WangY, LiuL, et al. Research progress on sirtuins family members and cell senescence. Eur J Med Chem. 2020;193:112207.

[36] MortuzaR, ChenS, FengB, Sen S, ChakrabartiS. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PLoS One. 2013;8:e54514.

[37] LiS, SunD, ChenS, et al. UCP2-SIRT3 signaling relieved hyperglycemia-induced oxidative stress and senescence in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2024;65:14.

[38] ChengY, ZhangM, XuR, et al. p53 accelerates endothelial cell senescence in diabetic retinopathy by enhancing FoxO3a ubiquitylation and degradation via UBE2L6. Exp Gerontol. 2024;188:112391.

[39] BalkaKR, LouisC, SaundersTL, et al. TBK1 and IKKϵ act redundantly to mediate STING-induced NF-κB responses in myeloid cells. Cell Rep. 2020;31:107492.

[40] LiuH, GhoshS, VaidyaT, et al. Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy. JCI Insight. 2023;8:e168945.

[41] ShoshaE, XuZ, NarayananSP, et al. Mechanisms of Diabetes-induced endothelial cell senescence: role of Arginase 1. Int J Mol Sci. 2018;19:1215.

[42] OubahaM, Miloudi K, DejdaA, et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Transl Med. 2016;8:362ra144.

[43] ChenQ, TangL, ZhangY, et al. STING up-regulates VEGF expression in oxidative stress-induced senescence of retinal pigment epithelium via NF-κB/HIF-1α pathway. Life Sci. 2022;293:120089.

[44] WangY, TsengY, ChenK, et al. Dasatinib plus quercetin alleviates choroid neovascularization by reducing the cellular senescence burden in the RPE-Choroid. Invest Ophthalmol Vis Sci. 2023;64:39.

[45] SreekumarPG, HintonDR, KannanR. The emerging role of senescence in ocular disease. Oxid Med Cell Longev. 2020;2020:2583601.

[46] WangH, Ramshekar A, CungT, et al. 7-Ketocholesterol promotes retinal pigment epithelium senescence and fibrosis of choroidal neovascularization via IQGAP1 phosphorylation-dependent signaling. Int J Mol Sci. 2023;24:10276.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.