Skip to main content
SpringerLink
Log in

Compromised mechanical homeostasis in arterial aging and associated cardiovascular consequences

  • Original Paper
  • Published:
Biomechanics and Modeling in Mechanobiology Aims and scope Submit manuscript

Abstract

Aging leads to central artery stiffening and associated hemodynamic sequelae. Because healthy arteries exhibit differential geometry, composition, and mechanical behaviors along the central vasculature, we sought to determine whether wall structure and mechanical function differ across five vascular regions—the ascending and descending thoracic aorta, suprarenal and infrarenal abdominal aorta, and common carotid artery—in 20 versus 100-week-old male wild-type mice. Notwithstanding generally consistent changes across these regions, including a marked thickening of the arterial wall, diminished in vivo axial stretch, and loss of elastic energy storage capacity, the degree of changes tended to be slightly greater in abdominal than in thoracic or carotid vessels. Likely due to the long half-life of vascular elastin, most mechanical changes in the arterial wall resulted largely from a distributed increase in collagen, including thicker fibers in the media, and localized increases in glycosaminoglycans. Changes within the central arteries associated with significant increases in central pulse pressure and adverse changes in the left ventricle, including increased cardiac mass and decreased diastolic function. Given the similar half-life of vascular elastin in mice and humans but very different life-spans, there are important differences in the aging of central vessels across these species. Nevertheless, the common finding of aberrant matrix remodeling contributing to a compromised mechanical homeostasis suggests that studies of central artery aging in the mouse can provide insight into mechanisms and treatment strategies for the many adverse effects of vascular aging in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Arribas SM, Hinek A, Gonzalez MC (2006) Elastic fibres and vascular structure in hypertension. Pharmacol Ther 111:771–791

    Article  Google Scholar 

  • Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S (2004) Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hyperten 17:23S–30S

    Article  Google Scholar 

  • Baek S, Gleason RL, Rajagopal KR, Humphrey JD (2007) Theory of small on large: potential utility in computations of fluid-solid interactions in arteries. Comput Methods Appl Mech Eng 196:3070–3078

    Article  MathSciNet  Google Scholar 

  • Bellini C, Ferruzzi J, Roccabianca S, Di Martino ES, Humphrey JD (2014) A microstructurally motivated model of arterial wall mechanics with mechanobiological implications. Annl Biomed Eng 42:488–502

    Article  Google Scholar 

  • Bellini C, Kristofik NJ, Bersi MR, Kyriakides TR, Humphrey JD (2017) A hidden structural vulnerability in the thrombospondin-2 deficient aorta increases the propensity to intramural delamination. J Mech Behav Biomed Mater 71:397–406

    Article  Google Scholar 

  • Bersi MR, Collins MJ, Wilson E, Humphrey JD (2012) Disparate changes in the mechanical properties of murine carotid arteries and aorta in response to chronic infusion of angiotensin-II. Int. J. Adv. Eng. Sci. Appl. Math. 4:228–240

    Article  MathSciNet  Google Scholar 

  • Bersi MR, Bellini C, Wu J, Harrison DG, Humphrey JD (2016) Excessive adventitial remodeling leads to maladaptive aortic function in angiotensin-induced hypertension. Hypertension 67:890–896

    Article  Google Scholar 

  • Bersi MR, Khosravi R, Wujciak AJ, Harrison DG, Humphrey JD (2017) Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension. J R Soc Interface 14:20170327

    Article  Google Scholar 

  • Boos CJ, Vincent E, Mellor A, Woods DR, New C, Cruttenden R, Barlow M, Cooke M, Deighton K, Scott P, Clarke S, O’Hara J (2017) The effect of high altitude on central blood pressure and arterial stiffness. J Hum Hyperten 31:715–719

    Article  Google Scholar 

  • Capell BC, Olive M, Erdos MR, Collins F (2008) A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. PNAS 105:15902–15907

    Article  Google Scholar 

  • Coquand-Gandit M, Jacob MP, Fhayli W (2017) Chronic treatment with Minoxidil induces elastic fiber neosynthesis and functional improvement in the aorta of aged mice. Rejuven Res 20:218–230

    Article  Google Scholar 

  • Cuomo F, Roccabianca S, Dillon-Murphy D, Xiao N, Humphrey JD, Figueroa CA (2017) Effects of age-associated regional changes in aortic stiffness on human hemodynamics revealed by computational modeling. PLoS ONE 12:e0173177

    Article  Google Scholar 

  • Davis EC (1993) Stability of elastin in the developing mouse aorta: a quantitative radioautographic study. Histochemistry 100:17–26

    Article  Google Scholar 

  • Davis PH, Dawson JD, Riley WA, Lauer RM (2001) Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age. Circulation 104:2815–2819

    Article  Google Scholar 

  • Demiray H (1992) Wave propagation through a viscous fluid contained in a prestressed thin elastic tube. Int J Eng Sci 30:1607–1620

    Article  MathSciNet  Google Scholar 

  • Eberth JF, Gresham VC, Reddy AK, Popovic N, Wilson E, Humphrey JD (2009) Importance of pulsatility in hypertensive carotid artery growth and remodeling. J Hyperten 27:2010–2021

    Article  Google Scholar 

  • Eberth JF, Popovic N, Gresham V, Wilson E, Humphrey JD (2010) Time course of carotid artery growth and remodeling in response to altered pulsatility. Am J Physiol 299:H1875–1883

    Google Scholar 

  • Eberth JF, Cardamone L, Humphrey JD (2011) Evolving biaxial mechanical properties of mouse carotid arteries in hypertension. J Biomech 44:2532–2537

    Article  Google Scholar 

  • Ferruzzi J, Collins MJ, Yeh AT, Humphrey JD (2011a) Mechanical assessment of elastin integrity in fibrillin-1-deficient carotid arteries: implications for Marfan syndrome. Cardiovasc Res 92:287–295

    Article  Google Scholar 

  • Ferruzzi J, Vorp DA, Humphrey JD (2011b) On constitutive descriptors of the biaxial mechanical behavior of human abdominal aorta and aneurysms. J R Soc Interface 8:435–450

    Article  Google Scholar 

  • Ferruzzi J, Bersi MR, Humphrey JD (2013) Biomechanical phenotyping of central arteries in health and disease: advantages of and methods for murine models. Annl Biomed Eng 41:1311–1330

    Article  Google Scholar 

  • Ferruzzi J, Bersi MR, Uman S, Yanagisawa H, Humphrey JD (2015) Decreased energy storage, not increased material stiffness, characterizes central artery dysfunction in fibulin-5 deficiency independent of sex. J Biomech Eng 137:0310071–03100714

    Article  Google Scholar 

  • Ferruzzi J, Bersi MR, Mecham RP, Ramirez F, Yanagisawa H, Tellides G, Humphrey JD (2016a) Loss of elastic fiber integrity compromises common carotid function: Implications for vascular aging. Artery Res 14:41–52

    Article  Google Scholar 

  • Ferruzzi J, Murtada S-I, Li G, Jiao Y, Uman S, Ting MY, Tellides G, Humphrey JD (2016b) Pharmacologically improved contractility protects against aortic dissection in mice with disrupted transforming growth factor-beta signaling despite compromised extracellular matrix properties. ATVB 36:919–927

    Google Scholar 

  • Ferruzzi J, Di Achille P, Mikush N, Sinusas AJ, Tellides G, Humphrey JD (2018) Combining in vivo and in vitro biomechanical data reveals key roles of perivascular tethering in central artery function (submitted)

  • Fleenor BS, Marshall KD, Durrant JR, Lesniewski LA, Seals DR (2010) Arterial stiffening with ageing is associated with transforming growth factor-\(\beta \)1-related changes in adventitial collagen: reversal by aerobic exercise. J Physiol 588(20):3971–3982

    Article  Google Scholar 

  • Fleenor BS, Seals DR, Zigler ML, Sindler AL (2012) Superoxide-lowering therapy with Tempol reverses arterial dysfunction with aging in mice. Aging Cell 11:269–276

    Article  Google Scholar 

  • Gleason RL, Gray SP, Wilson E, Humphrey JD (2004) A multiaxial computer-controlled organ culture and biomechanical device for mouse carotid arteries. ASME J Biomech Eng 126:787–795

    Article  Google Scholar 

  • Humphrey JD (2002) Cardiovascular solid mechanics: cells, tissues, and organs. Springer, New York

    Book  Google Scholar 

  • Humphrey JD (2008) Vascular adaptation and mechanical homeostasis at tissue, cellular, and sub-cellular levels. Cell Biochem Biophys 50:53–78

    Article  Google Scholar 

  • Humphrey JD, Eberth JF, Dye WW, Gleason RL (2009) Fundamental role of axial stress in compensatory adaptations by arteries. J Biomech 42:1–8

    Article  Google Scholar 

  • Humphrey JD, Dufrense E, Schwartz MA (2014) Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol 15:802–812

    Article  Google Scholar 

  • Humphrey JD, Harrison DG, Figueroa CA, Lacolley P, Laurent S (2016) Central artery stiffness in hypertension and aging. A problem with cause and consequence. Circ Res 118:379–381

    Article  Google Scholar 

  • Kuang SQ, Geng L, Prakash SK, Cao JM, Guo S, Villamizar C, Kwartler CS, Peters AM, Brasier AR, Milewicz DM (2013) Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade. Arterioscler Thromb Vasc Biol 33:2172–2179

    Article  Google Scholar 

  • Lacolley P, Safar ME, Regnault V, Frohlich ED (2009) Angiotensin II, mechanotransduction, and pulsatile arterial hemodynamics in hypertension. Am J Physiol 297:H1567–1575

    Article  Google Scholar 

  • Lakatta EG, Wang M, Najjar SS (2009) Arterial aging and subclinical arterial disease are fundamentally intertwined at macroscopic and microscopic levels. Med Clin N Am 93:583–604

    Article  Google Scholar 

  • Latorre M, Humphrey JD (2018) Modeling mechano-driven and immuno-mediated aortic maladaptation in hypertension. Biomech Model Mechanobiol (accepted)

  • Laurent S, Boutouyrie P (2015) The structural factor of hypertension: large and small artery alterations. Circ Res 116:1007–1021

    Article  Google Scholar 

  • Le VP, Stoka KV, Yanagisawa H, Wagenseil JE (2014) Fibulin-5 null mice with decreased arterial compliance maintain normal systolic left ventricular function, but not diastolic function during maturation. Physiol Rep 2:e00257

    Article  Google Scholar 

  • Lesniewski LA, Durrant JR, Connell ML, Henson GD, Black AD, Donato AJ, Seals DR (2011) Aerobic exercise reverses arterial inflammation with aging in mice. Am J Physiol 301:H1025–1032

    Google Scholar 

  • Nilsson PM, Boutouyrie P, Cunha P, Kotsis V, Narkiewicz K, Parati G, Rietzschel E, Scuteri A, Laurent S (2013) Early vascular ageing in translation: from laboratory investigations to clinical applications in cardiovascular prevention. J Hyperten 31:1517–1526

    Article  Google Scholar 

  • O’Rourke MF, Hashimoto J (2007) Mechanical factors in arterial aging: a clinical perspective. JACC 50:1–13

    Article  Google Scholar 

  • Pezet M, Jacob MP, Escoubet B et al (2008) Elastin haploinsufficiency induces alternate aging processes in the aorta. Rejuven Res 11:97–112

    Article  Google Scholar 

  • Rammos C, Hendgen-Cotta UB, Deenen R, Pohl J, Stock P, Hinzmann C, Kelm M, Rassef T (2014) Age-related vascular gene expression profiling in mice. Mechan Ageing Dev 135:15–23

    Article  Google Scholar 

  • Roccabianca S, Bellini C, Humphrey JD (2014) Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial mechanics and mechanobiology. J R Soc Interface 11:20140397

    Article  Google Scholar 

  • Roccabianca S, Figueroa CA, Tellides G, Humphrey JD (2014b) Quantification of regional differences in aortic stiffness in the aging human. J Mech Behav Biomed Mater 29:618–634

    Article  Google Scholar 

  • Rodriguez-Feo JA, de Klein Sluijter JP, de Kleijn DP, Pasterkamp G (2005) Modulation of collagen turnover in cardiovascular disease. Curr Pharm Des 11:2501–2514

    Article  Google Scholar 

  • Safar ME (2009) Arterial aging—hemodynamic changes and therapeutic optics. Nat Rev Cardiol 7:442–449

    Article  Google Scholar 

  • Sherratt MJ (2009) Tissue elasticity and the ageing elastic fibre. Age 31:305–325

    Article  Google Scholar 

  • Steppan J, Sikka G, Jandu S, Barodka V, Halushka MK, Flavahan NA, Belkin AM, Nyhan D, Butlin M, Avolio A, Berkowitz DE, Santhanam L (2014) Exercise, vascular stiffness, and tissue transglutaminase. J Am Heart Assoc 3:e000599

    Article  Google Scholar 

  • Varga R, Eriksson M, Erdos MR, Olive M, Harten I, Kolodgie F, Capell BC, Cheng J, Faddah D, Perkins S, Avallone H, San H, Qu X, Ganesh S, Gordon LB, Virmani R, Wight TN, Nabel EG, Collins F (2006) Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson–Gilford progeria syndrome. PNAS 103:3250–3255

    Article  Google Scholar 

  • Wagenseil JE, Mecham RP (2009) Vascular extracellular matrix and arterial mechanics. Physiol Rev 89:957–898

    Article  Google Scholar 

  • Wan W, Gleason RL (2013) Dysfunction in elastic fiber formation in fibulin-5 mull mice abrogates the evolution in mechanical response of carotid arteries during maturation. Am J Physiol 304:H674–686

    Article  Google Scholar 

  • Weiszäcker HW, Lambert H, Pasclae K (1983) Analysis of the passive mechanical properties of rat arteries. J Biomech 16:703–715

    Article  Google Scholar 

  • Wheeler JB, Mukherjee R, Stroud RE, Jones JA, Ikonomidis JS (2015) Relation of murine thoracic aortic structural and cellular changes with aging to passive and active mechanical properties. J Am Heart Assoc 4:e001744

    Article  Google Scholar 

  • Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, Madhur MS, Chen W, Harrison DG (2014) Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res 114:616–625

    Article  Google Scholar 

  • Zhang P, Huang A, Ferruzzi J, Mecham RP, Starcher BC, Tellides G, Humphrey JD, Giordano FJ, Niklason LE, Sessa WC (2012) Inhibition of microRNA-29 enhances elastin levels in cells haploinsufficient for elastin and bioengineered vessels—brief report. ATVB 32:756–759

    Google Scholar 

Download references

Acknowledgements

This work was supported, in part, by grants from the National Institutes of Health (R01 HL105297 and P01 HL134605). We thank Nikki Mikush (Staff, Yale School of Medicine) who acquired the ultrasound data and Thomas Stockdale (Visiting Student, University of Cambridge School of Clinical Medicine) who contributed to the early ultrasound analysis.

Author information

Author notes

  1. J. Ferruzzi

    Present address: Department of Biomedical Engineering, Boston University, Boston, MA, USA

Authors and Affiliations

  1. Department of Biomedical Engineering, Malone Engineering Center, Yale University, 55 Prospect Street, New Haven, CT, 06520, USA

    J. Ferruzzi, D. Madziva, A. W. Caulk & J. D. Humphrey

  2. Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA

    G. Tellides & J. D. Humphrey

  3. Department of Surgery, Yale School of Medicine, New Haven, CT, USA

    G. Tellides

Authors
  1. J. Ferruzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Madziva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. W. Caulk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Tellides
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. D. Humphrey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. D. Humphrey.

Ethics declarations

Conflicts of interest

All authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (pdf 769 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ferruzzi, J., Madziva, D., Caulk, A.W. et al. Compromised mechanical homeostasis in arterial aging and associated cardiovascular consequences. Biomech Model Mechanobiol 17, 1281–1295 (2018). https://doi.org/10.1007/s10237-018-1026-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10237-018-1026-7

Keywords

Search

Navigation