CCL4 Contributes to Aging Related Angiogenic Insufficiency Through Activating Oxidative Stress and Endothelial Inflammation

Overview

Journal Angiogenesis

Publisher Springer

Specialty Hematology

Date 2024 May 13

PMID 38739303

Authors

Ting-Ting Chang

Liang-Yu Lin

Ching Chen

Jaw-Wen Chen

Affiliations

Soon will be listed here.

Abstract

Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging.

Citing Articles

Immune and Metabolic Mechanisms of Endothelial Dysfunction.

Kopaliani I, Elsaid B, Speier S, Deussen A Int J Mol Sci. 2025; 25(24.

PMID: 39769104 PMC: 11728141. DOI: 10.3390/ijms252413337.

The Multifaceted Role of Endothelial Sirt1 in Vascular Aging: An Update.

Campagna R, Mazzanti L, Pompei V, Alia S, Vignini A, Emanuelli M Cells. 2024; 13(17.

PMID: 39273039 PMC: 11394039. DOI: 10.3390/cells13171469.

References

Huang J, Hou B, Zhang S, Wang M, Lu X, Wang Q . The Protective Effect of Adiponectin-Transfected Endothelial Progenitor Cells on Cognitive Function in D-Galactose-Induced Aging Rats. Neural Plast. 2020; 2020:1273198. PMC: 7125484. DOI: 10.1155/2020/1273198. View

Brandes R, Fleming I, Busse R . Endothelial aging. Cardiovasc Res. 2005; 66(2):286-94. DOI: 10.1016/j.cardiores.2004.12.027. View

Finkel T . The metabolic regulation of aging. Nat Med. 2015; 21(12):1416-23. DOI: 10.1038/nm.3998. View

Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I . Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest. 1998; 101(6):1219-24. PMC: 508675. DOI: 10.1172/JCI1277. View

Rea I, Gibson D, McGilligan V, McNerlan S, Alexander H, Ross O . Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front Immunol. 2018; 9:586. PMC: 5900450. DOI: 10.3389/fimmu.2018.00586. View

Huo L, Zheng Z, Huang J, Li R, Li J, Li J . Transcranial Direct Current Stimulation Enhances Episodic Memory in Healthy Older Adults by Modulating Retrieval-Specific Activation. Neural Plast. 2020; 2020:8883046. PMC: 7735856. DOI: 10.1155/2020/8883046. View

Maier R, Weger M, Haller-Schober E, El-Shabrawi Y, Wedrich A, Theisl A . Multiplex bead analysis of vitreous and serum concentrations of inflammatory and proangiogenic factors in diabetic patients. Mol Vis. 2008; 14:637-43. PMC: 2276180. View

Hanifi-Moghaddam P, Kappler S, Seissler J, Muller-Scholze S, Martin S, Roep B . Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus. Diabet Med. 2006; 23(2):156-63. DOI: 10.1111/j.1464-5491.2005.01743.x. View

Ryden A, Faresjo M . Altered immune profile from pre-diabetes to manifestation of type 1 diabetes. Diabetes Res Clin Pract. 2013; 100(1):74-84. DOI: 10.1016/j.diabres.2013.01.014. View

Lodi P, Garrett D, Kuszewski J, Tsang M, Weatherbee J, Leonard W . High-resolution solution structure of the beta chemokine hMIP-1 beta by multidimensional NMR. Science. 1994; 263(5154):1762-7. DOI: 10.1126/science.8134838. View

10.

Choudhury S, Liu Y, Clark A, Pang I . Caspase-7: a critical mediator of optic nerve injury-induced retinal ganglion cell death. Mol Neurodegener. 2015; 10:40. PMC: 4550044. DOI: 10.1186/s13024-015-0039-2. View

11.

Kadir R, Alwjwaj M, Othman O, Rakkar K, Sprigg N, Bath P . Inhibition of oxidative stress delays senescence and augments functional capacity of endothelial progenitor cells. Brain Res. 2022; 1787:147925. DOI: 10.1016/j.brainres.2022.147925. View

12.

Guo Y, Li P, Gao L, Zhang J, Yang Z, Bledsoe G . Kallistatin reduces vascular senescence and aging by regulating microRNA-34a-SIRT1 pathway. Aging Cell. 2017; 16(4):837-846. PMC: 5506400. DOI: 10.1111/acel.12615. View

13.

Chang T, Lin L, Chen J . Inhibition of macrophage inflammatory protein-1β improves endothelial progenitor cell function and ischemia-induced angiogenesis in diabetes. Angiogenesis. 2018; 22(1):53-65. DOI: 10.1007/s10456-018-9636-3. View

14.

Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T . Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275(5302):964-7. DOI: 10.1126/science.275.5302.964. View

14.

Wang H, Kuo C, Chung C, Lin W, Wang Y, Lin T . Rapid and Accurate Discrimination of Subspecies Based on Matrix-Assisted Laser Desorption Ionization-Time of Flight Spectrum and Machine Learning Algorithms. Biomedicines. 2023; 11(1). PMC: 9856018. DOI: 10.3390/biomedicines11010045. View

15.

Hazarika S, Dokun A, Li Y, Popel A, Kontos C, Annex B . Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1. Circ Res. 2007; 101(9):948-56. DOI: 10.1161/CIRCRESAHA.107.160630. View

16.

Chang T, Yang H, Chen C, Chen J . CCL4 Inhibition in Atherosclerosis: Effects on Plaque Stability, Endothelial Cell Adhesiveness, and Macrophages Activation. Int J Mol Sci. 2020; 21(18). PMC: 7555143. DOI: 10.3390/ijms21186567. View

17.

Lakatta E, Levy D . Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003; 107(2):346-54. DOI: 10.1161/01.cir.0000048893.62841.f7. View

18.

Wu Y, Fu C, Li B, Liu C, He Z, Li X . Bradykinin Protects Human Endothelial Progenitor Cells from High-Glucose-Induced Senescence through B2 Receptor-Mediated Activation of the Akt/eNOS Signalling Pathway. J Diabetes Res. 2021; 2021:6626627. PMC: 8452971. DOI: 10.1155/2021/6626627. View