Stiffness of large arteries has been long recognized as a significant determinant of pulse pressure. However, it is only in recent decades, with the accumulation of longitudinal data from large and varied epidemiological studies of morbidity and mortality associated with cardiovascular disease, that it has emerged as an independent predictor of cardiovascular risk. This has generated substantial interest in investigations related to intrinsic causative and associated factors responsible for the alteration of mechanical properties of the arterial wall, with the aim to uncover specific pathways that could be interrogated to prevent or reverse arterial stiffening. Much has been written on the haemodynamic relevance of arterial stiffness in terms of the quantification of pulsatile relationships of blood pressure and flow in conduit arteries. Indeed, much of this early work regarded blood vessels as passive elastic conduits, with the endothelial layer considered as an inactive lining of the lumen and as an interface to flowing blood. However, recent advances in molecular biology and increased technological sophistication for the detection of low concentrations of biochemical compounds have elucidated the highly important regulatory role of the endothelial cell affecting vascular function. These techniques have enabled research into the interaction of the underlying passive mechanical properties of the arterial wall with the active cellular and molecular processes that regulate the local environment of the load-bearing components. This review addresses these emerging concepts.

1.
Mitchell JR, Schwartz CJ: Relationship between arterial disease in different sites. A study of the aorta and coronary, carotid, and iliac arteries. Br Med J 1962;1:1293-1301.
2.
Nichols WW, O'Rourke MF, Vlachopoulos C: McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, ed 6. London, Hodder Arnold, 2011.
3.
O'Rourke MF, Hashimoto J: Mechanical factors in arterial aging: a clinical perspective. J Am Coll Cardiol 2007;50:1-13.
4.
Pickering G: Arteriosclerosis and atherosclerosis. The need for clear thinking. Am J Med 1963;34:7-18.
5.
Wilkinson IB, McEniery CM, Cockcroft JR: Arteriosclerosis and atherosclerosis: guilty by association. Hypertension 2009;54:1213-1215.
6.
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;107:139-146.
7.
Bailey AJ: Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev 2001;122:735-755.
8.
Greenwald SE: Ageing of the conduit arteries. J Pathol 2007;211:157-172.
9.
Najjar SS, Scuteri A, Lakatta EG: Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005;46:454-462.
10.
Franklin SS, Jacobs MJ, Wong ND, L'Italien GJ, Lapuerta P: Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension 2001;37:869-874.
11.
Amery A, Fagard R, Guo C, Staessen J, Thijs L: Isolated systolic hypertension in the elderly: an epidemiologic review. Am J Med 1991;90:64S-70S.
12.
Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, et al: Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006;113:657-663.
13.
Franklin SS: Pulse pressure as a risk factor. Clin Exp Hypertens 2004;26:645-652.
14.
Arnett DK, Evans GW, Riley WA: Arterial stiffness: a new cardiovascular risk factor? Am J Epidemiol 1994;140:669-682.
15.
Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999;99:2434-2439.
16.
Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, et al: Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236-1241.
17.
Wang TJ: Assessing the role of circulating, genetic, and imaging biomarkers in cardiovascular risk prediction. Circulation 2011;123:551-565.
18.
Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG: Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation 2002;106:2085-2090.
19.
Avolio A, Jones D, Tafazzoli-Shadpour M: Quantification of alterations in structure and function of elastin in the arterial media. Hypertension 1998;32:170-175.
20.
Santhanam L, Tuday EC, Webb AK, Dowzicky P, Kim JH, Oh YJ, et al: Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness. Circ Res 2010;107:117-125.
21.
Intaglietta M, Frangos JA: Introduction: mechanotransduction and translational medicine workshop. J Intern Med 2006;259:336-338.
22.
Lehoux S, Castier Y, Tedgui A: Molecular mechanisms of the vascular responses to haemodynamic forces. J Intern Med 2006;259:381-392.
23.
Bergel DH: The static elastic properties of the arterial wall. J Physiol 1961;156:445-457.
24.
Cox RH: Pressure dependence of the mechanical properties of arteries in vivo. Am J Physiol 1975;229:1371-1375.
25.
Dobrin PB, Mrkvicka R: Estimating the elastic modulus of non-atherosclerotic elastic arteries. J Hypertens Suppl 1992;10:S7-S10.
26.
Bauer RD, Busse R, Schabert A: Mechanical properties of arteries. Biorheology 1982;19:409-424.
27.
O'Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE: Clinical applications of arterial stiffness; definitions and reference values. Am J Hypertens 2002;15:426-444.
28.
Gosling RG, Budge MM: Terminology for describing the elastic behavior of arteries. Hypertension 2003;41:1180-1182.
29.
Chirinos JA: Arterial stiffness: basic concepts and measurement techniques. J Cardiovasc Transl Res 2012;5:243-255.
30.
Albaladejo P, Copie X, Boutouyrie P, Laloux B, Declere AD, Smulyan H, et al: Heart rate, arterial stiffness, and wave reflections in paced patients. Hypertension 2001;38:949-952.
31.
Tan I, Butlin M, Liu YY, Ng K, Avolio AP: Heart rate dependence of aortic pulse wave velocity at different arterial pressures in rats. Hypertension 2012;60:528-533.
32.
Wang YX, Fitch RM: Vascular stiffness: measurements, mechanisms and implications. Curr Vasc Pharmacol 2004;2:379-384.
33.
Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ: The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol 2000;525:263-270.
34.
Wolinsky H, Glagov S: Structural basis for the static mechanical properties of the aortic media. Circ Res 1964;14:400-413.
35.
Wolinsky H, Glagov S: A lamellar unit of aortic medial structure and function in mammals. Circ Res 1967;20:99-111.
36.
Wolinsky H, Glagov S: Comparison of abdominal and thoracic aortic medial structure in mammals. Deviation of man from the usual pattern. Circ Res 1969;25:677-686.
37.
Lillie MA, Armstrong TE, Gerard SG, Shadwick RE, Gosline JM: Contribution of elastin and collagen to the inflation response of the pig thoracic aorta: assessing elastin's role in mechanical homeostasis. J Biomech 2012;45:2133-2141.
38.
Lillie MA, Shadwick RE, Gosline JM: Mechanical anisotropy of inflated elastic tissue from the pig aorta. J Biomech 2010;43:2070-2078.
39.
Gosline JM, Shadwick RE: The mechanical properties of fin whale arteries are explained by novel connective tissue designs. J Exp Biol 1996;199:985-997.
40.
Shadwick RE: Mechanical design in arteries. J Exp Biol 1999;202:3305-3313.
41.
Westerhof N, Lankhaar JW, Westerhof BE: The arterial Windkessel. Med Biol Eng Comput 2009;47:131-141.
42.
Wang JJ, O'Brien AB, Shrive NG, Parker KH, Tyberg JV: Time-domain representation of ventricular-arterial coupling as a windkessel and wave system. Am J Physiol Heart Circ Physiol 2003;284:H1358-H1368.
43.
Learoyd BM, Taylor MG: Alterations with age in the viscoelastic properties of human arterial walls. Circ Res 1966;18:278-292.
44.
Avolio AP, Deng FQ, Li WQ, Luo YF, Huang ZD, Xing LF, et al: Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation 1985;71:202-210.
45.
Lee HY, Oh BH: Aging and arterial stiffness. Circ J 2010;74:2257-2262.
46.
Zieman SJ, Melenovsky V, Kass DA: Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25:932-943.
47.
Avolio A, Butlin M, Liu YY, Viegas K, Avadhanam B, Lindesay G: Regulation of arterial stiffness: cellular, molecular and neurogenic mechanisms. Artery Res 2011;5:122-127.
48.
Wagenseil JE, Mecham RP: Vascular extracellular matrix and arterial mechanics. Physiol Rev 2009;89:957-989.
49.
Gosline J, Lillie M, Carrington E, Guerette P, Ortlepp C, Savage K: Elastic proteins: biological roles and mechanical properties. Philos Trans R Soc Lond B Biol Sci 2002;357:121-132.
50.
Elvin CM, Carr AG, Huson MG, Maxwell JM, Pearson RD, Vuocolo T, et al: Synthesis and properties of crosslinked recombinant pro-resilin. Nature 2005;437:999-1002.
51.
Shapiro SD, Endicott SK, Province MA, Pierce JA, Campbell EJ: Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. J Clin Invest 1991;87:1828-1834.
52.
Martyn CN, Greenwald SE: A hypothesis about a mechanism for the programming of blood pressure and vascular disease in early life. Clin Exp Pharmacol Physiol 2001;28:948-951.
53.
Le VP, Knutsen RH, Mecham RP, Wagenseil JE: Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice. Am J Physiol Heart Circ Physiol 2011;301:H221-H229.
54.
Nakashima Y, Shiokawa Y, Sueishi K: Alterations of elastic architecture in human aortic dissecting aneurysm. Lab Invest 1990;62:751-760.
55.
Wagenseil JE, Mecham RP: Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res 2012;5:264-273.
56.
Perret-Guillaume C, Joly L, Benetos A: Heart rate as a risk factor for cardiovascular disease. Prog Cardiovasc Dis 2009;52:6-10.
57.
Benetos A, Adamopoulos C, Bureau JM, Temmar M, Labat C, Bean K, et al: Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation 2002;105:1202-1207.
58.
Lantelme P, Mestre C, Lievre M, Gressard A, Milon H: Heart rate: an important confounder of pulse wave velocity assessment. Hypertension 2002;39:1083-1087.
59.
Mangoni AA, Mircoli L, Giannattasio C, Ferrari AU, Mancia G: Heart rate-dependence of arterial distensibility in vivo. J Hypertens 1996;14:897-901.
60.
Mircoli L, Mangoni AA, Giannattasio C, Mancia G, Ferrari AU: Heart rate-dependent stiffening of large arteries in intact and sympathectomized rats. Hypertension 1999;34:598-602.
61.
Bergel DH: The dynamic elastic properties of the arterial wall. J Physiol 1961;156:458-469.
62.
Salvucci FP, Schiavone J, Craiem D, Barra JG: Arterial wall mechanics as a function of heart rate: role of vascular smooth muscle. J Phys Conf Ser 2007;90:1-7.
63.
Luft FC: Molecular mechanisms of arterial stiffness: new insights. J Am Soc Hypertens 2012;6:436-438.
64.
Park S, Lakatta EG: Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med J 2012;53:258-261.
65.
Maki-Petaja KM, Elkhawad M, Cheriyan J, Joshi FR, Ostor AJ, Hall FC, et al: Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation 2012;126:2473-2480.
66.
Resnick N, Gimbrone MA Jr: Hemodynamic forces are complex regulators of endothelial gene expression. FASEB J 1995;9:874-882.
67.
Ziegler T, Bouzourene K, Harrison VJ, Brunner HR, Hayoz D: Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler Thromb Vasc Biol 1998;18:686-692.
68.
Peng X, Haldar S, Deshpande S, Irani K, Kass DA: Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium. Hypertension 2003;41:378-381.
69.
Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft JR: Nitric oxide regulates local arterial distensibility in vivo. Circulation 2002;105:213-217.
70.
Schmitt M, Avolio A, Qasem A, McEniery CM, Butlin M, Wilkinson IB, et al: Basal NO locally modulates human iliac artery function in vivo. Hypertension 2005;46:227-231.
71.
McEniery CM, Qasem A, Schmitt M, Avolio AP, Cockcroft JR, Wilkinson IB: Endothelin-1 regulates arterial pulse wave velocity in vivo. J Am Coll Cardiol 2003;42:1975-1981.
72.
Schmitt M, Qasem A, McEniery C, Wilkinson IB, Tatarinoff V, Noble K, et al: Role of natriuretic peptides in regulation of conduit artery distensibility. Am J Physiol Heart Circ Physiol 2004;287:H1167-H1171.
73.
Cox RH: Comparison of arterial wall mechanics in normotensive and spontaneously hypertensive rats. Am J Physiol 1979;237:H159-H167.
74.
Dobrin PB, Rovick AA: Influence of vascular smooth muscle on contractile mechanics and elasticity of arteries. Am J Physiol 1969;217:1644-1651.
75.
Armentano RL, Barra JG, Santana DB, Pessana FM, Graf S, Craiem D, et al: Smart damping modulation of carotid wall energetics in human hypertension: effects of angiotensin-converting enzyme inhibition. Hypertension 2006;47:384-390.
76.
Campbell JH, Campbell GR: Smooth muscle phenotypic modulation - a personal experience. Arterioscler Thromb Vasc Biol 2012;32:1784-1789.
77.
Johnson RC, Leopold JA, Loscalzo J: Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res 2006;99:1044-1059.
78.
Persy V, D'Haese P: Vascular calcification and bone disease: the calcification paradox. Trends Mol Med 2009;15:405-416.
79.
Giallauria F, Ling SM, Schreiber C, Maggio M, Shetty V, Muller D, et al: Arterial stiffness and bone demineralization: the Baltimore longitudinal study of aging. Am J Hypertens 2011;24:970-975.
80.
Atkinson J: Age-related medial elastocalcinosis in arteries: mechanisms, animal models, and physiological consequences. J Appl Physiol 2008;105:1643-1651.
81.
Dao HH, Essalihi R, Bouvet C, Moreau P: Evolution and modulation of age-related medial elastocalcinosis: impact on large artery stiffness and isolated systolic hypertension. Cardiovasc Res 2005;66:307-317.
82.
Niederhoffer N, Lartaud-Idjouadiene I, Giummelly P, Duvivier C, Peslin R, Atkinson J: Calcification of medial elastic fibers and aortic elasticity. Hypertension 1997;29:999-1006.
83.
Zagura M, Serg M, Kampus P, Zilmer M, Eha J, Unt E, et al: Aortic stiffness and vitamin D are independent markers of aortic calcification in patients with peripheral arterial disease and in healthy subjects. Eur J Vasc Endovasc Surg 2011;42:689-695.
84.
Ng K, Hildreth CM, Phillips JK, Avolio AP: Aortic stiffness is associated with vascular calcification and remodeling in a chronic kidney disease rat model. Am J Physiol Renal Physiol 2011;300:F1431-F1436.
85.
Johnson KA, Polewski M, Terkeltaub RA: Transglutaminase 2 is central to induction of the arterial calcification program by smooth muscle cells. Circ Res 2008;102:529-537.
86.
Jiang L, Zhang J, Monticone RE, Telljohann R, Wu J, Wang M, et al: Calpain-1 regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells facilitates age-associated aortic wall calcification and fibrosis. Hypertension 2012;60:1192-1199.
87.
McCurley A, Pires PW, Bender SB, Aronovitz M, Zhao MJ, Metzger D, et al: Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med 2012;18:1429-1433.
88.
Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S: Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens 2004;17:23S-30S.
89.
Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, et al: Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 2001;104:1464-1470.
90.
Sell DR, Monnier VM: Molecular basis of arterial stiffening: role of glycation - a mini-review. Gerontology 2012;58:227-237.
91.
Galis ZS, Khatri JJ: Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002;90:251-262.
92.
Lopez-Andres N, Calvier L, Labat C, Fay R, Diez J, Benetos A, et al: Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice. Hypertension 2013;61:120-129.
93.
Lima B, Forrester MT, Hess DT, Stamler JS: S-nitrosylation in cardiovascular signaling. Circ Res 2010;106:633-646.
94.
Lai TS, Hausladen A, Slaughter TF, Eu JP, Stamler JS, Greenberg CS: Calcium regulates S-nitrosylation, denitrosylation, and activity of tissue transglutaminase. Biochemistry 2001;40:4904-4910.
95.
Kim JH, Bugaj LJ, Oh YJ, Bivalacqua TJ, Ryoo S, Soucy KG, et al: Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. J Appl Physiol 2009;107:1249-1257.
96.
Nichols WW, McDonald DA: Wave-velocity in the proximal aorta. Med Biol Eng 1972;10:327-335.
97.
Barra JG, Armentano RL, Levenson J, Fischer EI, Pichel RH, Simon A: Assessment of smooth muscle contribution to descending thoracic aortic elastic mechanics in conscious dogs. Circ Res 1993;73:1040-1050.
98.
Pagani M, Schwartz PJ, Bishop VS, Malliani A: Reflex sympathetic changes in aortic diastolic pressure-diameter relationship. Am J Physiol 1975;229:286-290.
99.
Lacolley P, Glaser E, Challande P, Boutouyrie P, Mignot JP, Duriez M, et al: Structural changes and in situ aortic pressure-diameter relationship in long-term chemical-sympathectomized rats. Am J Physiol 1995;269:H407-H416.
100.
Mangoni AA, Mircoli L, Giannattasio C, Mancia G, Ferrari AU: Effect of sympathectomy on mechanical properties of common carotid and femoral arteries. Hypertension 1997;30:1085-1088.
101.
Nakao M, Nomura K, Karita K, Nishikitani M, Yano E: Relationship between brachial-ankle pulse wave velocity and heart rate variability in young Japanese men. Hypertens Res 2004;27:925-931.
102.
Swierblewska E, Hering D, Kara T, Kunicka K, Kruszewski P, Bieniaszewski L, et al: An independent relationship between muscle sympathetic nerve activity and pulse wave velocity in normal humans. J Hypertens 2010;28:979-984.
103.
Levy BI, Michel JB, Salzmann JL, Devissaguet M, Safar ME: Remodeling of heart and arteries by chronic converting enzyme inhibition in spontaneously hypertensive rats. Am J Hypertens 1991;4:240S-245S.
104.
Benetos A, Levy BI, Lacolley P, Taillard F, Duriez M, Safar ME: Role of angiotensin II and bradykinin on aortic collagen following converting enzyme inhibition in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 1997;17:3196-3201.
105.
Wang M, Khazan B, Lakatta EG: Central arterial aging and angiotensin II signaling. Curr Hypertens Rev 2010;6:266-281.
106.
Ng K, Butlin M, Avolio AP: Persistent effect of early, brief angiotensin-converting enzyme inhibition on segmental pressure dependency of aortic stiffness in spontaneously hypertensive rats. J Hypertens 2012;30:1782-1790.
107.
Mahmud A, Feely J: Effect of angiotensin ii receptor blockade on arterial stiffness: beyond blood pressure reduction. Am J Hypertens 2002;15:1092-1095.
108.
Frimodt-Moller M, Kamper AL, Strandgaard S, Kreiner S, Nielsen AH: Beneficial effects on arterial stiffness and pulse-wave reflection of combined enalapril and candesartan in chronic kidney disease - a randomized trial. PLoS One 2012;7:e41757.
109.
Paulis L, Becker ST, Lucht K, Schwengel K, Slavic S, Kaschina E, et al: Direct angiotensin II type 2 receptor stimulation in Nomega-nitro-L-arginine-methyl ester-induced hypertension: the effect on pulse wave velocity and aortic remodeling. Hypertension 2012;59:485-492.
110.
Lacolley P, Challande P, Osborne-Pellegrin M, Regnault V: Genetics and pathophysiology of arterial stiffness. Cardiovasc Res 2009;81:637-648.
111.
Mitchell GF, Verwoert GC, Tarasov KV, Isaacs A, Smith AV, Yasmin, et al: Common genetic variation in the 3′-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium. Circ Cardiovasc Genet 2012;5:81-90.
112.
Herrera VL, Pasion KA, Moran AM, Ruiz-Opazo N: Dahl (S×R) congenic strain analysis confirms and defines a chromosome 5 female-specific blood pressure quantitative trait locus to <7 Mbp. PLoS One 2012;7:e42214.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.