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Age-related vascular stiffening: causes and consequences
Open accessAbstract
Arterial stiffening occurs with age and is closely associated with the progression of cardiovascular disease. Stiffening is most often studied at the level of the whole vessel because increased stiffness of the large arteries can impose increased strain on the heart leading to heart failure. Interestingly, however, recent evidence suggests that the impact of increased vessel stiffening extends beyond the tissue scale and can also have deleterious microscale effects on cellular function. Altered extracellular matrix (ECM) architecture has been recognized as a key component of the pre-atherogenic state. Here, the underlying causes of age-related vessel stiffening are discussed, focusing on age-related crosslinking of the ECM proteins as well as through increased matrix deposition. Methods to measure vessel stiffening at both the macro- and microscale are described, spanning from the pulse wave velocity measurements performed clinically to microscale measurements performed largely in research laboratories. Additionally, recent work investigating how arterial stiffness and the changes in the ECM associated with stiffening contributed to endothelial dysfunction will be reviewed. We will highlight how changes in ECM protein composition contribute to atherosclerosis in the vessel wall. Lastly, we will discuss very recent work that demonstrates endothelial cells (ECs) are mechano-sensitive to arterial stiffening, where changes in stiffness can directly impact EC health. Overall, recent studies suggest that stiffening is an important clinical target not only because of potential deleterious effects on the heart but also because it promotes cellular level dysfunction in the vessel wall, contributing to a pathological atherosclerotic state.
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“EC dysfunction has been shown to strongly affect arterial stiffness via cellular adhesion molecules (CAMs), matrix metalloproteinases (MMPs) and collagen molecules (COLs)67–71.”
From An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging (2021) · cites this paper as [68]
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“, 2018), and cell-cell communication between vascular endothelial cells (Kohn et al., 2015).”
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“Furthermore, aging is well-known to be associated with increased vascular stiffness of whole arteries(Kohn et al., 2015), but the effect of aging on endothelial stiffness is not defined.”
BackgroundNanotechnology meets medicine: applications of atomic force microscopy in disease
Matias, Z., Lopes, C. S., Santos, N. C., & Carvalho, F. A. (2025) · Biophysical Reviews · doi:10.1007/s12551-025-01306-w · Cited by 19
“Kohn et al. focused on the impact of aerobic exercise on atherosclerosis, showing lower macro-level stiffness for aged mice undergoing aerobic exercise, compared to those with sedentary lifestyle (Kohn et al. 2015, 2016).”
Freidoonimehr, N., Chin, R. C., Zander, A. C., & Arjomandi, M. (2021) · Journal of Biomechanical Engineering · doi:10.1115/1.4051923 · Cited by 14
Harikrishnan, K., Prabhu, S. S., & Balasubramanian, N. (2022) · PLoS ONE · doi:10.1371/journal.pone.0270063 · Cited by 16
da Silva, D. V. T., Baião, D. D. S., de Almeida, C. C., & Paschoalin, V. M. F. (2023) · Nutrients · doi:10.3390/nu15112618 · Cited by 15
“Aging is associated with lower vessel wall elastin-to-collagen ratios, due to progressive elastic fiber degeneration and increased collagen synthesis [17].”
BackgroundMcNeill, M. C., Chee, F. L. M., Ebrahimighaei, R., Sala‐Newby, G. B., Newby, A. C., Hathway, T., Annaiah, A. S., Joseph, S., Carrabba, M., & Bond, M. (2024) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2023.12.005 · Cited by 16
Fujita, M., Sasada, M., Iyoda, T., & Fukai, F. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126591 · Cited by 14
van der Graaf, A. M., Paauw, N. D., Toering, T. J., Feelisch, M., Faas, M. M., Sutton, T. R., Minnion, M., Lefrandt, J. D., Scherjon, S. A., Franx, A., et al. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00010.2016 · Cited by 13
“Increased arterial stiffness is a result of aging (changes in extracellular matrix composition) (23) and is associated with hypertension, diabetes mellitus, atherosclerosis, and renal failure (35, 40).”
Microvascular Network and Its Endothelial Cells in the Human Iris
Yang, H., Yu, P. K., Cringle, S. J., Sun, X., & Yu, D. (2017) · Current Eye Research · doi:10.1080/02713683.2017.1379544 · Cited by 14
“Aging is known to be associated with mechanical heterogeneity of the sub-endothelial matrix(54) and cell function is known to be associated with matrix stiffness.(55) Whilst we do not know whether aging and the associated matrix stiffness is a contributing factor to the centralized location of the endothelial nuclei,…”
BackgroundAdvanced glycation end products as a source of artifacts in immunoenzymatic methods
Kuzan, A., Chwiłkowska, A., Maksymowicz, K., Bronowicka-Szydełko, A., Stach, K., Pezowicz, C. A., & Gamian, A. (2018) · Glycoconjugate Journal · doi:10.1007/s10719-017-9805-4 · Cited by 14
“It is known that they constitute over 50% of the dry weight of the artery [5] and that the quantity of this tissue may bemodulated by different processes, for example atherogenesis.”
BackgroundSchaarup, J. R., Christensen, M. S., Hulmán, Á., Hansen, C. S., Vistisen, D., Tabák, Á. G., Witte, D. R., & Bjerg, L. (2023) · GeroScience · doi:10.1007/s11357-023-00762-0 · Cited by 14
“First, changes in autonomic nervous function and arterial stiffness could have a common root cause, ageing that leads to the reduction in both autonomic response and elasticity in the arterial wall [34, 35].”
BackgroundMechanisms of endothelial stiffening in dyslipidemia and aging: Oxidized lipids and shear stress
Master, E. L., Ahn, S. J., & Levitan, I. (2020) · Current topics in membranes · doi:10.1016/bs.ctm.2020.08.006 · Cited by 14
“, 2011), our results show increased stiffness in the sub-endothelial layer in 22–25 month old mice, a commonly accepted age for advanced aged mice (Kohn et al., 2015) versus younger mice (4–6 months old) (17 ± 2 versus 7 ± 1kPa in aged versus young mice).”
BackgroundResultLai, A., Zhou, Y., Chheang, C., Mirabedini, A., Mirzaalikhan, Y., Noonan, J. E., Watson, A. M. D., Dayawansa, N. H., Huang, W., Khanmohammadi, M., et al. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123932 · Cited by 13
An Overview of Vascular Dysfunction and Determinants: The Case of Children of African Ancestry
Matjuda, E. N., Engwa, G. A., Sewani-Rusike, C. R., & Nkeh-Chungag, B. N. (2021) · Frontiers in Pediatrics · doi:10.3389/fped.2021.769589 · Cited by 15
McCallinhart, P. E., Lee, Y. U., Lee, A. Y., Anghelescu, M., Tonniges, J. R., Calomeni, E. P., Agarwal, G., Lincoln, J., & Trask, A. J. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1154454 · Cited by 13
“Extracellular matrix remodeling underlies age-related aortic stiffening in most models (Lakatta and Levy, 2003; Zieman et al., 2005; Kohn et al., 2015).”
BackgroundBalloon Catheter-Integrated Piezoelectric Micropyramid Arrays for Measuring Vascular Stiffness
Kang, Y., Lee, J., Park, S., Kim, J., Kim, S. I., & Ryu, W. (2023) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.3c00700 · Cited by 13
Xu, M., Wang, W., Chen, R., Zhou, L., Hu, H., Qiao, G., Wang, L., Liu, X., Wang, Q.-H., Ai, Y., et al. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1158098 · Cited by 13
“Systemic in fl ammation, characterized by elevated levels of in fl ammatory markers/mediators in the bloodstream, can result in endothelial dysfunction (48), impairment of microvasomotor function (49), and reduced arterial elasticity (50).”
BackgroundFraile‐Μartinez, O., León-Oliva, D. D., Boaru, D. L., Castro-Martinez, P. D., Montero, C. G., Barrena-Blázquez, S., García-García, J., García‐Honduvilla, N., Álvarez‐Mon, M., López-González, L., et al. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1345459 · Cited by 15
“Aged blood vessels show decreased compliance, elasticity, and distensibility, as well as increased stiffness (Kohn et al., 2015).”
BackgroundRole of Changes in State of Bound Water and Tissue Stiffness in Development of Age-Related Diseases
Kerch, G. (2020) · Polymers · doi:10.3390/polym12061362 · Cited by 13
Vascular Aging in the Invertebrate Chordate, Botryllus schlosseri
Rodriguez, D., Taketa, D. A., Madhu, R., Kassmer, S. H., Loerke, D., Valentine, M. T., & Tomaso, A. W. D. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.626827 · Cited by 13
“The aged cell phenotype we observe in Botryllus also resembles that of vascular smooth muscle cells by highly expressing alpha actin (ACTN1) and collagen I (COL1A1) which may contribute to vessel stiffening (Urry, 1971; Urry and Onishi, 1974; Otto et al., 1999; Fleenor et al., 2010, 2012; Kohn et al., 2015).”
BackgroundTurner, M. P., Zhao, Y., Abdelkarim, D., Liu, P., Spence, J. S., Hutchison, J. L., Sivakolundu, D. K., Thomas, B. P., Hubbard, N. A., Xu, C., et al. (2022) · Cerebral Cortex · doi:10.1093/cercor/bhac057 · Cited by 13
Diana, G., Scardulla, F., Puleo, S., Pasta, S., & D’Acquisto, L. (2025) · Sensors · doi:10.3390/s25113301 · Cited by 13
Fanni, B. M., Antonuccio, M. N., Pizzuto, A., Berti, S. L., Santoro, G., & Celi, S. (2023) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd10030109 · Cited by 12
“It can provide insight into its structural integrity, is strongly related to the patient’s age [56,57], and can also be used as a bio-marker for disease progression [58,59].”
BackgroundEffect of Patient Characteristics on Vessel Enhancement at Lower Extremity CT Angiography
Masuda, T., Nakaura, T., Funama, Y., Sato, T., Higaki, T., Kiguchi, M., Yamashita, Y., Imada, N., & Awai, K. (2018) · Korean Journal of Radiology · doi:10.3348/kjr.2018.19.2.265 · Cited by 12
“Arterial stiffness due to biological aging and arteriosclerosis (20) is related to the blood flow and may help to explain the effect of the age on popliteal artery enhancement.”
BackgroundIendaltseva, O., Orlova, V. V., Mummery, C. L., Danen, E. H. J., & Schmidt, T. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.05.001 · Cited by 12
Visualizing antithrombin-binding 3- O -sulfated heparan sulfate motifs on cell surfaces
Kalita, M., Chua, J. S., Boothello, R. S., Joice, A. C., Antelope, O., Roy, A., Babu, P. V. A., Saijoh, Y., Desai, U. R., & Kuberan, B. (2020) · Chemical Communications · doi:10.1039/d0cc05893a · Cited by 12
A potential role of autophagy-mediated vascular senescence in the pathophysiology of HFpEF
Sanhueza‐Olivares, F., Troncoso, M. F., la Fuente, F. P.-D., Martinez-Bilbao, J., Riquelme, J. A., Norambuena‐Soto, I., Villa, M., Lavandero, S., Castro, P., & Chiong, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1057349 · Cited by 13
Jia, X., Yang, Q., Gao, C., Chen, X., Li, Y., Su, H., Zheng, Y., Zhang, S., Wang, Z., Wang, H., et al. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30349 · Cited by 11
“…multiple cell types, including vas- cular smooth muscle cells (VSMCs) and extracellular matrix (ECM), and ECM is an important factor determining the mechanical prop- erties or stiffness of blood vessels wall (Ebrahimi, 2009; Kohn et al., 2015; Matsumoto & Nagayama, 2012; Wagenseil & Mecham, 2009).”
BackgroundCappelletti, S., Caimi, A., Caldiroli, A., Baroni, I., Votta, E., Riboldi, S. A., Marrocco-Trischitta, M. M., Redaelli, A. C. L., & Sturla, F. (2022) · Quantitative Imaging in Medicine and Surgery · doi:10.21037/qims-21-987 · Cited by 11
Shayor, A. A., Kabir, M. E., Rifath, M. S. A., Rashid, A. B., & Oh, K. W. (2024) · Sensors · doi:10.3390/s24185872 · Cited by 11
Role of macrophages in vascular calcification: From the perspective of homeostasis
Dong, R., Ji, Z., Wang, M., & Ma, G. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113635 · Cited by 11
Santini, F., Pansini, M., Paar, M. H., Yates, D. P., Langenickel, T., Bremerich, J., Bieri, O., & Schubert, T. B. (2020) · Journal of Cardiovascular Magnetic Resonance · doi:10.1186/s12968-020-00669-1 · Cited by 11
“the finding that the arterial wall stiffens with age and leads to a lower compliance [17].”
BackgroundCaçoilo, A., Rusinek, H., & Weickenmeier, J. (2022) · Engineering With Computers · doi:10.1007/s00366-022-01700-y · Cited by 12
“Limited cerebral vasoreactivity and lower cerebral pulsatility gradually creates a chronic state of white matter hypoperfusion [81].”
BackgroundLumen segmentation using a Mask R-CNN in carotid arteries with stenotic atherosclerotic plaque
Kiernan, M., Mukaddim, R. A., Mitchell, C., Maybock, J., Wilbrand, S. M., Dempsey, R. J., & Varghese, T. (2023) · Ultrasonics · doi:10.1016/j.ultras.2023.107193 · Cited by 11
Bastounis, E. E., Ortega, F. E., Serrano, R., & Theriot, J. A. (2018) · Journal of Visualized Experiments · doi:10.3791/57361 · Cited by 11
Metadata
- Authors
- Kohn, J. C., Lampi, M. C., & Reinhart-King, C. A.
- Affiliations
- Cornell University (US)
- Venue
- Frontiers in Genetics
- Publisher
- Frontiers Media SA
- Published
- 2015-03-30
- Volume
- 06
- Pages
- 112-112
- ISSN
- 1664-8021 (ISSN-L)
- PMC
- PMC4396535
- OpenAlex
- W2048903244
- Cited by
- 440
- References
- 229
- Citations by year
- 2026: 45 · 2025: 36 · 2024: 58 · 2023: 60 · 2022: 46 · 2021: 51 · 2020: 36 · 2019: 29 · 2018: 40 · 2017: 26 · 2016: 11 · 2015: 1
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (1435755, 2013165170, 2013155462)
- National Heart, Lung, and Blood Institute (R21HL097296, HL097296)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Physical Sciences › Engineering › Biomedical Engineering › Elasticity and Material Modeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- arterial stiffening, aging, extracellular matrix, matrix deposition, pulse wave velocity, endothelial dysfunction, atherosclerosis, cardiovascular disease, heart failure
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