Exploration of Cardiology

Table 2. Structural and cellular drivers of vascular stiffness.

Driver	Molecular/cellular basis	Effect on arterial wall	References
Elastin degradation	↑ MMP activity, mechanical fatigue	Loss of elasticity, ↑ stiffness	[19, 20, 24, 25]
Collagen accumulation	↑ Synthesis, AGE-mediated cross-linking	Increased rigidity, ↓ compliance	[19, 20, 24–26]
VSMC phenotypic switch	Contractile → synthetic phenotype	↑ ECM production, fibrosis	[21, 22, 27, 30]
Vascular calcification	↑ Phosphate, osteogenic VSMC differentiation	Medial calcification, ↑ pulse wave velocity	[21, 22, 25, 27]

Return to article view

AGE: advanced glycation end product; ECM: extracellular matrix; MMP: matrix metalloproteinase; VSMC: vascular smooth muscle cell.

Declarations

Acknowledgments

During the preparation of this work, the authors used ChatGPT (OpenAI) to assist with composing and refining the figures. After using the tool, authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Author contributions

MCÇ: Conceptualization, Investigation, Writing—original draft. MK: Conceptualization, Writing—review & editing. AB: Conceptualization, Investigation, Writing—original draft. MY: Writing—review & editing. LB: Supervision, Validation. YK: Supervision, Validation. All of the authors contributed to planning, conducting, and reporting of the work. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

No financial funding was received for this study.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Herrera MD, Mingorance C, Rodríguez-Rodríguez R, Alvarez de Sotomayor M. Endothelial dysfunction and aging: an update. Ageing Res Rev. 2010;9:142–52. [DOI] [PubMed]

Behringer EJ. Impact of aging on vascular ion channels: perspectives and knowledge gaps across major organ systems. Am J Physiol Heart Circ Physiol. 2023;325:H1012–38. [DOI] [PubMed] [PMC]

Wang X, He B. Endothelial dysfunction: molecular mechanisms and clinical implications. MedComm (2020). 2024;5:e651. [DOI] [PubMed] [PMC]

Ungvari Z, Tarantini S, Kiss T, Wren JD, Giles CB, Griffin CT, et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol. 2018;15:555–65. [DOI] [PubMed] [PMC]

Widmer RJ, Lerman A. Endothelial dysfunction and cardiovascular disease. Glob Cardiol Sci Pract. 2014;2014:291–308. [DOI] [PubMed] [PMC]

Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33:829–37. [DOI] [PubMed] [PMC]

Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA. 1999;282:2035–42. [DOI] [PubMed]

Curry FE, Adamson RH. Endothelial glycocalyx: permeability barrier and mechanosensor. Ann Biomed Eng. 2012;40:828–39. [DOI] [PubMed] [PMC]

Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25:932–43. [DOI] [PubMed]

10.

Wagenseil JE, Mecham RP. Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res. 2012;5:264–73. [DOI] [PubMed] [PMC]

11.

Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30:445–8. [DOI] [PubMed]

12.

Félétou M, Vanhoutte PM. Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol. 2006;26:1215–25. [DOI] [PubMed]

13.

Sarmah N, Nauli AM, Ally A, Nauli SM. Interactions among Endothelial Nitric Oxide Synthase, Cardiovascular System, and Nociception during Physiological and Pathophysiological States. Molecules. 2022;27:2835. [DOI] [PubMed] [PMC]

14.

Sibal L, Agarwal SC, Home PD, Boger RH. The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease. Curr Cardiol Rev. 2010;6:82–90. [DOI] [PubMed] [PMC]

15.

Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res. 2005;66:286–94. [DOI] [PubMed]

16.

Donato AJ, Morgan RG, Walker AE, Lesniewski LA. Cellular and molecular biology of aging endothelial cells. J Mol Cell Cardiol. 2015;89:122–35. [DOI] [PubMed] [PMC]

17.

Wojtacha JJ, Morawin B, Wawrzyniak-Gramacka E, Tylutka A, de Freitas AKE, Zembron-Lacny A. Endothelial Dysfunction with Aging: Does Sex Matter? Int J Mol Sci. 2024;25:12203. [DOI] [PubMed] [PMC]

18.

Han Y, Kim SY. Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics. Exp Mol Med. 2023;55:1–12. [DOI] [PubMed] [PMC]

19.

Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation. 2003;107:139–46. [DOI] [PubMed]

20.

Herzog MJ, Müller P, Lechner K, Stiebler M, Arndt P, Kunz M, et al. Arterial stiffness and vascular aging: mechanisms, prevention, and therapy. Signal Transduct Target Ther. 2025;10:282. [DOI] [PubMed] [PMC]

21.

Tang H, Chen A, Zhang H, Gao X, Kong X, Zhang J. Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases. Cells. 2022;11:4060. [DOI] [PubMed] [PMC]

22.

Aguilar VM, Paul A, Lazarko D, Levitan I. Paradigms of endothelial stiffening in cardiovascular disease and vascular aging. Front Physiol. 2023;13:1081119. [DOI] [PubMed] [PMC]

23.

Kim H. Arterial stiffness and hypertension. Clin Hypertens. 2023;29:31. [DOI] [PubMed] [PMC]

24.

Wang M, Zhang J, Jiang L, Spinetti G, Pintus G, Monticone R, et al. Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension. 2007;50:219–27. [DOI] [PubMed]

25.

Fleenor BS, Marshall KD, Durrant JR, Lesniewski LA, Seals DR. Arterial stiffening with ageing is associated with transforming growth factor-β1-related changes in adventitial collagen: reversal by aerobic exercise. J Physiol. 2010;588:3971–82. [DOI] [PubMed] [PMC]

26.

McEniery CM, Wilkinson IB, Avolio AP. Age, hypertension and arterial function. Clin Exp Pharmacol Physiol. 2007;34:665–71. [DOI] [PubMed]

27.

Du L, Rodgers J, Gharraee N, Gary O, Shazly T, Eberth JF, et al. Endothelial dysfunction promotes age-related reorganization of collagen fibers and alters aortic biomechanics in mice. Am J Physiol Heart Circ Physiol. 2025;328:H900–14. [DOI] [PubMed] [PMC]

28.

Rodríguez-Mañas L, El-Assar M, Vallejo S, López-Dóriga P, Solís J, Petidier R, et al. Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation. Aging Cell. 2009;8:226–38. [DOI] [PubMed]

29.

Li Q, Qian Z, Huang Y, Yang X, Yang J, Xiao N, et al. Mechanisms of endothelial senescence and vascular aging. Biogerontology. 2025;26:128. [DOI] [PubMed]

30.

Gardner SE, Humphry M, Bennett MR, Clarke MCH. Senescent Vascular Smooth Muscle Cells Drive Inflammation Through an Interleukin-1α-Dependent Senescence-Associated Secretory Phenotype. Arterioscler Thromb Vasc Biol. 2015;35:1963–74. [DOI] [PubMed] [PMC]

31.

Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, et al. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol. 2011;301:H363–72. [DOI] [PubMed] [PMC]

32.

Ungvari Z, Sonntag WE, Csiszar A. Mitochondria and aging in the vascular system. J Mol Med (Berl). 2010;88:1021–7. [DOI] [PubMed] [PMC]

33.

Guzik TJ, Touyz RM. Oxidative Stress, Inflammation, and Vascular Aging in Hypertension. Hypertension. 2017;70:660–7. [DOI] [PubMed]

34.

Kane AE, Sinclair DA. Sirtuins and NAD⁺in the Development and Treatment of Metabolic and Cardiovascular Diseases. Circ Res. 2018;123:868–85. [DOI] [PubMed] [PMC]

35.

Liu J, Bi X, Chen T, Zhang Q, Wang S, Chiu J, et al. Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression. Cell Death Dis. 2015;6:e1827. [DOI] [PubMed] [PMC]

36.

Alao J, Legon L, Rallis C. Crosstalk between the mTOR and DNA Damage Response Pathways in Fission Yeast. Cells. 2021;10:305. [DOI] [PubMed] [PMC]

37.

Yamakuchi M, Hashiguchi T. Endothelial Cell Aging: How miRNAs Contribute? J Clin Med. 2018;7:170. [DOI] [PubMed] [PMC]

38.

Ding Y, Tang X, Chen H, Liu D. Epigenetic Regulation of Vascular Aging and Age-Related Vascular Diseases. Adv Exp Med Biol. 2018;1086:55–75. [DOI] [PubMed]

39.

Zhang L, Xia C, Yang Y, Sun F, Zhang Y, Wang H, et al. DNA methylation and histone post-translational modifications in atherosclerosis and a novel perspective for epigenetic therapy. Cell Commun Signal. 2023;21:344. [DOI] [PubMed] [PMC]

40.

He S, Huang B, Xu F, Yang J, Li C, Liu F, et al. Functions and application of circRNAs in vascular aging and aging-related vascular diseases. J Nanobiotechnology. 2025;23:216. [DOI] [PubMed] [PMC]

41.

Huang X, Huang X, Pan M, Lin J, Xie L. Effect of early endothelial function improvement on subclinical target organ damage in hypertensives. Sci Rep. 2024;14:16078. [DOI] [PubMed] [PMC]

42.

Boutouyrie P, Chowienczyk P, Humphrey JD, Mitchell GF. Arterial Stiffness and Cardiovascular Risk in Hypertension. Circ Res. 2021;128:864–86. [DOI] [PubMed]

43.

Maruhashi T, Higashi Y. Current topic of vascular function in hypertension in 2023-2024. Hypertens Res. 2024;47:3310–7. [DOI] [PubMed] [PMC]

44.

Medina-Leyte DJ, Zepeda-García O, Domínguez-Pérez M, González-Garrido A, Villarreal-Molina T, Jacobo-Albavera L. Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches. Int J Mol Sci. 2021;22:3850. [DOI] [PubMed] [PMC]

45.

Kim M, Kim H, Lim W, Seo J, Kim S, Kim M, et al. Association between arterial stiffness and left ventricular diastolic function: A large population-based cross-sectional study. Front Cardiovasc Med. 2022;9:1001248. [DOI] [PubMed] [PMC]

46.

Sun H, Wu Z, Nie X, Bian J. Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Front Pharmacol. 2020;10:1568. [DOI] [PubMed] [PMC]

47.

Arabi SM, Chambari M, Bahrami LS, Hadi S, Sahebkar A. Statin Therapy and Flow-Mediated Dilation: A Systematic Review and Dose-Response Meta-Analysis Using the GRADE of Data from Randomized Controlled Trials. Curr Hypertens Rev. 2024;20:90–100. [DOI] [PubMed]

48.

Altun I, Oz F, Arkaya SC, Altun I, Bilge AK, Umman B, et al. Effect of statins on endothelial function in patients with acute coronary syndrome: a prospective study using adhesion molecules and flow-mediated dilatation. J Clin Med Res. 2014;6:354–61. [DOI] [PubMed] [PMC]

49.

Chen B, Guo J, Ye H, Wang X, Feng Y. Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review). Mol Med Rep. 2024;29:73. [DOI] [PubMed] [PMC]

50.

Mallareddy M, Parikh CR, Peixoto AJ. Effect of angiotensin-converting enzyme inhibitors on arterial stiffness in hypertension: systematic review and meta-analysis. J Clin Hypertens (Greenwich). 2006;8:398–403. [DOI] [PubMed] [PMC]

51.

Shahin Y, Khan JA, Chetter I. Angiotensin converting enzyme inhibitors effect on arterial stiffness and wave reflections: a meta-analysis and meta-regression of randomised controlled trials. Atherosclerosis. 2012;221:18–33. [DOI] [PubMed]

52.

Bovolini A, Costa-Brito AR, Martins F, Furtado GE, Mendonça GV, Vila-Chã C. Impact of Exercise on Vascular Function in Middle-Aged and Older Adults: A Scoping Review. Sports (Basel). 2022;10:208. [DOI] [PubMed] [PMC]

53.

Tao X, Chen Y, Zhen K, Ren S, Lv Y, Yu L. Effect of continuous aerobic exercise on endothelial function: A systematic review and meta-analysis of randomized controlled trials. Front Physiol. 2023;14:1043108. [DOI] [PubMed] [PMC]

54.

Shannon OM, Mendes I, Köchl C, Mazidi M, Ashor AW, Rubele S, et al. Mediterranean Diet Increases Endothelial Function in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Nutr. 2020;150:1151–9. [DOI] [PubMed]

55.

Jones T, Dunn EL, Macdonald JH, Kubis H, McMahon N, Sandoo A. The Effects of Beetroot Juice on Blood Pressure, Microvascular Function and Large-Vessel Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Pilot Study in Healthy Older Adults. Nutrients. 2019;11:1792. [DOI] [PubMed] [PMC]

56.

Xu J, Hirai T, Koya D, Kitada M. Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches. J Clin Med. 2021;11:137. [DOI] [PubMed] [PMC]

57.

Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446–56. [DOI] [PubMed] [PMC]

58.

Roth L, Dogan S, Tuna BG, Aranyi T, Benitez S, Borrell-Pages M, et al. Pharmacological modulation of vascular ageing: A review from VascAgeNet. Ageing Res Rev. 2023;92:102122. [DOI] [PubMed]

59.

Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24:1246–56. [DOI] [PubMed] [PMC]

60.

Jylhävä J, Pedersen NL, Hägg S. Biological Age Predictors. EBioMedicine. 2017;21:29–36. [DOI] [PubMed] [PMC]

61.

Mozos I, Malainer C, Horbańczuk J, Gug C, Stoian D, Luca CT, et al. Inflammatory Markers for Arterial Stiffness in Cardiovascular Diseases. Front Immunol. 2017;8:1058. [DOI] [PubMed] [PMC]

62.

Safar ME, Jankowski P. Central blood pressure and hypertension: role in cardiovascular risk assessment. Clin Sci (Lond). 2009;116:273–82. [DOI] [PubMed]

63.

North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res. 2012;110:1097–108. [DOI] [PubMed] [PMC]

64.

Yusuf S, Joseph P, Rangarajan S, Islam S, Mente A, Hystad P, et al. Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study. Lancet. 2020;395:795–808. [DOI] [PubMed] [PMC]