Effects of Early-Life Stress on Whole-Blood Expression of Vascular Endothelial Dysfunction-Associated Genes
Vascular Endothelial Dysfunction-Associated Gene Profiles in Stress Models
DOI:
https://doi.org/10.22317/jcms.v12i4.2204Keywords:
Stress, Psychological, Endothelium, Vascular, Inflammation, Cardiovascular DiseasesAbstract
Objectives: Early-life stress (ELS) is linked to adult cardiovascular disease, but its immediate effects on adolescent vascular endothelial health remain poorly defined. Here, we evaluated whole-blood expression of vascular endothelial dysfunction-associated genes in ELS-exposed adolescent mice, as well as direct endothelial gene expression changes in dexamethasone-treated human umbilical vein endothelial cells (HUVECs).
Methods: BALB/c mice were paired for breeding in a 1:1 male-to-female ratio and allocated into control & experimental groups (6 pairs per group). Offspring from the experimental group underwent maternal separation (3 h /day, postnatal days 1–14) to induce ELS, while control litters remained undisturbed. A total of 24 offspring per group (12 males, 12 females per group) were used for subsequent evaluations. Whole blood from mice was used for gene expression analysis. In parallel, HUVECs were exposed to low-concentration (10 nM) and high-concentration (100 nM) dexamethasone. Target gene expression (Esm1/ESM1, E-selectin/E-SELECTIN, Cst3/CST3, ICAM1, VCAM1) was quantified by Quantitative PCR (qPCR) using the 2-∆∆ct method. Data were analyzed using unpaired t-tests for animal cohort comparisons. Statistical significance was set at p < 0.05. For in vitro HUVECs assays, target gene expression levels were calculated as fold changes relative to vehicle control.
Results: ELS significantly elevated whole-blood Cst3 (p = 0.003) and Esm1 (p = 0.02) expression in adolescent mice across the combined cohort, whereas E-selectin expression remained unaltered. Subgroup analyses revealed a significant transcriptional change in female ELS mice, characterized by an elevation in Cst3 (p = 0.005) and an upward trend in Esm1 (p = 0.060), while male ELS mice showed no significant alterations in any of the targets. Vascular endothelial dysfunction-associated gene expression exhibited concentration-associated differences following dexamethasone exposure. Under low-concentration conditions, CST3 (27.46-fold), ICAM1 (1.46-fold), and VCAM1 (1.41-fold) were upregulated, whereas E-SELECTIN (0.16-fold) and ESM1 (0.42-fold) were downregulated. Under high-concentration conditions, ESM1 (5.83-fold), VCAM1 (4.53-fold), and CST3 (1.61-fold) were upregulated, while ICAM1 (0.49-fold) and E-SELECTIN (0.20-fold) were downregulated.
Conclusion: ELS selectively modulated whole-blood expression of vascular endothelial dysfunction-associated genes in adolescent mice, while in the exploratory HUVECs experiment, dexamethasone exposure was associated with distinct gene-expression profiles at 10 nM and 100 nM. The study identified Cst3 as an exploratory candidate associated with the observed stress response. Future studies in both preclinical models and human adolescent cohorts are needed to confirm its mechanistic role and clinical relevance.
References
Chrousos GP, Gold PW. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. Jama. 1992;267(9):1244-1252.
Remmers MCC, Reijs RP, Hoebe CJPA. Defining and distinguishing early life stress, trauma, adversity, toxic and chronic stress and allostatic load: a descriptive review. Scand J Public Health. 2025;53(6):670-684.
Tan H, Zhou H, Chen J, Ren H, Guo Y, Jiang X. Association of early life adversity with cardiovascular disease and its potential mechanisms: a narrative review. Front public Heal. 2024;12:1341266.
Fagundes CP, Way B. Early-Life Stress and Adult Inflammation. Curr Dir Psychol Sci. 2014;23(4):277-283. doi:10.1177/0963721414535603
Jackson DB, Testa A, Woodward KP, Qureshi F, Ganson KT, Nagata JM. Adverse childhood experiences and cardiovascular risk among young adults: findings from the 2019 behavioral risk factor surveillance system. Int J Environ Res Public Health. 2022;19(18):11710.
Immanuel J, Yun S. Vascular Inflammatory Diseases and Endothelial Phenotypes. Cells. 2023;12(12). doi:10.3390/cells12121640
Xue J, Zhang Z, Sun Y, et al. Research progress and molecular mechanisms of endothelial cells inflammation in vascular-related diseases. J Inflamm Res. Published online 2023:3593-3617.
Djuric M, Nenadic I, Radisavljevic N, et al. The Influence of Anesthetics on the Functions of the Endothelium and Oxidative Stress: A Critical Review. Biomedicines. 2025;13(10). doi:10.3390/biomedicines13102357
Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol. 2015;7(11):719.
Wang Z, Yang Y, Wang Q, et al. Pathological mechanisms and clinical research progress of endothelial dysfunction. Front Cardiovasc Med. 2026;Volume 13. doi:10.3389/fcvm.2026.1749548
Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry. 2016;21(5):642-649.
Réus GZ, Dos Santos MAB, Abelaira HM, et al. Imipramine reverses alterations in cytokines and BDNF levels induced by maternal deprivation in adult rats. Behav Brain Res. 2013;242:40-46.
Nayak SS, Ameen D, Nobakht S, et al. The predictive value of endocan as a novel biomarker: an umbrella study on meta-analyses. Syst Rev. 2025;14(1):98. doi:10.1186/s13643-025-02858-4
Çimen T, Efe TH, Akyel A, et al. Human endothelial cell-specific molecule-1 (endocan) and coronary artery disease and microvascular angina. Angiology. 2016;67(9):846-853.
Chen J, Jiang L, Yu XH, et al. Endocan: A Key Player of Cardiovascular Disease. Front Cardiovasc Med. 2021;8:798699. doi:10.3389/fcvm.2021.798699
Moser S, Araschmid L, Panagiotou A, et al. Association of Endothelial Cell Activation with Acute Kidney Injury during Coronary Angiography and the Influence of Recombinant Human C1 Inhibitor—A Secondary Analysis of a Randomized, Placebo-Controlled, Double-Blind Trial. Biomedicines. 2024;12(9). doi:10.3390/biomedicines12091956
Horstman LL, Jy W, Jimenez JJ, Ahn YS. Endothelial microparticles as markers of endothelial dysfunction. Front biosci. 2004;9(1):118-135.
Singh V, Kaur R, Kumari P, Pasricha C, Singh R. ICAM-1 and VCAM-1: Gatekeepers in various inflammatory and cardiovascular disorders. Clin Chim Acta. 2023;548:117487. doi:https://doi.org/10.1016/j.cca.2023.117487
Lama E, Wang Y, Wu J, et al. Pathophysiological mechanisms and therapeutic potential of E-selectin in pulmonary arterial hypertension. Front Immunol. 2026;Volume 17. doi:10.3389/fimmu.2026.1754940
Maniwa K, Yano S, Sheikh AM, et al. Association between cystatin C gene polymorphism and the prevalence of white matter lesion in elderly healthy subjects. Sci Rep. 2020;10(1):4688. doi:10.1038/s41598-020-61383-7
Lee M, Saver JL, Huang WH, Chow J, Chang KH, Ovbiagele B. Impact of Elevated Cystatin C Level on Cardiovascular Disease Risk in Predominantly High Cardiovascular Risk Populations. Circ Cardiovasc Qual Outcomes. 2010;3(6):675-683. doi:10.1161/CIRCOUTCOMES.110.957696
Xiang L, Marshall Jr GD. Immunomodulatory effects of dexamethasone on gene expression of cytokine and stress hormone receptors in peripheral blood mononuclear cells. Int Immunopharmacol. 2013;17(3):556-560.
Barokah AN, Gürsoy İK, Dönmez MH, Fitremann J, Bayram A, Bayram KK. Long-Term Impact of Early-Life Stress on Hippocampal Apoptotic Gene Expression in BALB/c Mice. Neurochem Res. 2026;51(4):203. doi:10.1007/s11064-026-04822-7
Callaghan BL, Richardson R. Early-life stress affects extinction during critical periods of development: an analysis of the effects of maternal separation on extinction in adolescent rats. Stress. 2012;15(6):671-679.
Czarnabay D, Dalmago J, Martins AS, et al. Repeated three-hour maternal deprivation as a model of early-life stress alters maternal behavior, olfactory learning and neural development. Neurobiol Learn Mem. 2019;163:107040. doi:https://doi.org/10.1016/j.nlm.2019.107040
de Souza JA, da Silva MC, Costa FCO, et al. Early life stress induced by maternal separation during lactation alters the eating behavior and serotonin system in middle-aged rat female offspring. Pharmacol Biochem Behav. 2020;192:172908. doi:10.1016/j.pbb.2020.172908
Endo N, Makinodan M, Mannari-Sasagawa T, et al. The effects of maternal separation on behaviours under social-housing environments in adult male C57BL/6 mice. Sci Rep. 2021;11(1):527. doi:10.1038/s41598-020-80206-3
Ho DH, Burch ML, Musall B, Musall JB, Hyndman KA, Pollock JS. Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood. Am J Physiol Circ Physiol. 2016;310(9):H1267-H1274.
Balta S, Mikhailidis DP, Demirkol S, Ozturk C, Celik T, Iyisoy A. Endocan: a novel inflammatory indicator in cardiovascular disease? Atherosclerosis. 2015;243(1):339-343.
Balta S, Mikhailidis DP, Demirkol S, Celik T, Ozturk C, Iyisoy A. Endocan and atherosclerosis. Angiology. 2015;66(5):490.
Bidlan Megha, Kumar Mohit, Bhargava Anurag, Goel Vrinda, Kumar Vijay. Endocan, a Potential Biomarker of Endothelial Dysfunction: A Brief Overview. Angiology. 2026;77(7):799-807. doi:10.1177/00033197251356576
Kose M, Emet S, Akpinar TS, et al. Serum endocan level and the severity of coronary artery disease: a pilot study. Angiology. 2015;66(8):727-731.
Friedman EM, Williams DR, Singer BH, Ryff CD. Chronic discrimination predicts higher circulating levels of E-selectin in a national sample: the MIDUS study. Brain Behav Immun. 2009;23(5):684-692.
Kershaw KN, Lane-Cordova AD, Carnethon MR, Tindle HA, Liu K. Chronic stress and endothelial dysfunction: the multi-ethnic study of atherosclerosis (MESA). Am J Hypertens. 2017;30(1):75-80.
Habas K, Shang L. Alterations in intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in human endothelial cells. Tissue Cell. 2018;54:139-143.
Pober JS, Sessa WC. Inflammation and the blood microvascular system. Cold Spring Harb Perspect Biol. 2015;7(1):a016345.
Rostampour N, Fekri K, Hashemi-Dehkordi E, Obodiat M. Association between Vascular Endothelial Markers and Carotid Intima-Media Thickness in Children and Adolescents with Type 1 Diabetes Mellitus. J Clin Diagn Res. 2017;11(9):SC01-SC05. doi:10.7860/JCDR/2017/26623.10541
Peter K, Weirich U, Nordt TK, Ruef J, Bode C. Soluble vascular cell adhesion molecule-1 (VCAM-1) as potential marker of atherosclerosis. Thromb Haemost. 1999;82 Suppl 1:38-43.
Nagy EE, Puskás A, Kelemen P, et al. Elevated Serum Cystatin C and Decreased Cathepsin S/Cystatin C Ratio Are Associated with Severe Peripheral Arterial Disease and Polyvascular Involvement. Diagnostics. 2022;12(4). doi:10.3390/diagnostics12040833
Liu L, Wang H, Ning J, Han J, Yu C, Guan Q. The Predictability of Cystatin C for Peripheral Arterial Disease in Chinese Population with Type 2 Diabetes Mellitus. J Diabetes Res. 2022;2022(1):5064264. doi:https://doi.org/10.1155/2022/5064264
Arpegård J, Östergren J, De Faire U, Hansson LO, Svensson P. Cystatin C—a marker of peripheral atherosclerotic disease? Atherosclerosis. 2008;199(2):397-401.
Li Z, Wang S, Huo X, et al. Cystatin C expression is promoted by VEGFA blocking, with inhibitory effects on endothelial cell angiogenic functions including proliferation, migration, and chorioallantoic membrane angiogenesis. J Am Heart Assoc. 2018;7(21):e009167.
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Journal of Contemporary Medical Sciences
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
