Annals of Biomedical Engineering

, Volume 41, Issue 7, pp 1411–1427 | Cite as

High Wall Shear Stress and Spatial Gradients in Vascular Pathology: A Review

  • Jennifer M. Dolan
  • John Kolega
  • Hui Meng


Cardiovascular pathologies such as intracranial aneurysms (IAs) and atherosclerosis preferentially localize to bifurcations and curvatures where hemodynamics are complex. While extensive knowledge about low wall shear stress (WSS) has been generated in the past, due to its strong relevance to atherogenesis, high WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology as well, receiving renewed interests. As reviewed here, chronic high WSS not only stimulates adaptive outward remodeling, but also contributes to saccular IA formation (at bifurcation apices or outer curves) and atherosclerotic plaque destabilization (in stenosed vessels). Recent advances in understanding IA pathogenesis have shed new light on the role of high WSS in pathological vascular remodeling. In complex geometries, high WSS can couple with significant spatial WSS gradient (WSSG). A combination of high WSS and positive WSSG has been shown to trigger aneurysm initiation. Since endothelial cells (ECs) are sensors of WSS, we have begun to elucidate EC responses to high WSS alone and in combination with WSSG. Understanding such responses will provide insight into not only aneurysm formation, but also plaque destabilization and other vascular pathologies and potentially lead to improved strategies for disease management and novel targets for pharmacological intervention.


Intracranial aneurysm Aneurysm initiation Atherosclerosis Outward remodeling Vulnerable plaque Wall shear stress gradient Endothelial cell sensing Hemodynamics 



We thank Nicholas Liaw for critical review of the manuscript and assistance with figures, and Chris Martensen for assistance with figures and references. This work was supported by NIH grant R01NS064592 (awarded to H.M.).


  1. 1.
    Abruzzo, T., A. Kendler, R. Apkarian, M. Workman, J. C. Khoury, and H. J. Cloft. Cerebral aneurysm formation in nitric oxide synthase-3 knockout mice. Curr. Neurovasc. Res. 4:161–169, 2007.PubMedCrossRefGoogle Scholar
  2. 2.
    Alnaes, M. S., J. Isaksen, K. A. Mardal, B. Romner, M. K. Morgan, and T. Ingebrigtsen. Computation of hemodynamics in the circle of Willis. Stroke 38:2500–2505, 2007.PubMedCrossRefGoogle Scholar
  3. 3.
    Aoki, T., H. Kataoka, R. Ishibashi, K. Nozaki, K. Egashira, and N. Hashimoto. Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke 40:942–951, 2009.PubMedCrossRefGoogle Scholar
  4. 4.
    Aoki, T., H. Kataoka, R. Ishibashi, K. Nozaki, and N. Hashimoto. Cathepsin B, K, and S are expressed in cerebral aneurysms and promote the progression of cerebral aneurysms. Stroke 39:2603–2610, 2008.PubMedCrossRefGoogle Scholar
  5. 5.
    Aoki, T., H. Kataoka, M. Morimoto, K. Nozaki, and N. Hashimoto. Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats. Stroke 38:162–169, 2007.PubMedCrossRefGoogle Scholar
  6. 6.
    Aoki, T., H. Kataoka, M. Nishimura, R. Ishibashi, R. Morishita, and S. Miyamoto. Ets-1 promotes the progression of cerebral aneurysm by inducing the expression of MCP-1 in vascular smooth muscle cells. Gene Ther. 17:1117–1123, 2010.PubMedCrossRefGoogle Scholar
  7. 7.
    Aoki, T., H. Kataoka, M. Shimamura, H. Nakagami, K. Wakayama, T. Moriwaki, R. Ishibashi, K. Nozaki, R. Morishita, and N. Hashimoto. NF-kappaB is a key mediator of cerebral aneurysm formation. Circulation 116:2830–2840, 2007.PubMedCrossRefGoogle Scholar
  8. 8.
    Aoki, T., M. Nishimura, H. Kataoka, R. Ishibashi, K. Nozaki, and S. Miyamoto. Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS. Lab. Invest. 91:619–626, 2011.PubMedCrossRefGoogle Scholar
  9. 9.
    Aoki, T., M. Nishimura, T. Matsuoka, K. Yamamoto, T. Furuyashiki, H. Kataoka, S. Kitaoka, R. Ishibashi, A. Ishibazawa, S. Miyamoto, R. Morishita, J. Ando, N. Hashimoto, K. Nozaki, and S. Narumiya. PGE(2) -EP(2) signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-kappaB. Br. J. Pharmacol. 163:1237–1249, 2011.PubMedCrossRefGoogle Scholar
  10. 10.
    Bark, Jr., D. L., A. N. Para, and D. N. Ku. Correlation of thrombosis growth rate to pathological wall shear rate during platelet accumulation. Biotechnol. Bioeng. 109:2642–2650, 2012.PubMedCrossRefGoogle Scholar
  11. 11.
    Brown, Jr., R. D., D. O. Wiebers, and G. S. Forbes. Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemorrhage and relationship of lesions. J. Neurosurg. 73:859–863, 1990.PubMedCrossRefGoogle Scholar
  12. 12.
    Bruno, G., R. Todor, I. Lewis, and D. Chyatte. Vascular extracellular matrix remodeling in cerebral aneurysms. J. Neurosurg. 89:431–440, 1998.PubMedCrossRefGoogle Scholar
  13. 13.
    Burke, A., and G. A. Fitzgerald. Oxidative stress and smoking-induced vascular injury. Prog. Cardiovasc. Dis. 46:79–90, 2003.PubMedCrossRefGoogle Scholar
  14. 14.
    Caro, C. G., J. M. Fitz-Gerald, and R. C. Schroter. Atheroma and arterial wall shear. Observation, correlation and proposal of a shear dependent mass transfer mechanism for atherogenesis. Proc. R. Soc. Lond. B Biol. Sci. 177:109–159, 1971.PubMedCrossRefGoogle Scholar
  15. 15.
    Castier, Y., R. P. Brandes, G. Leseche, A. Tedgui, and S. Lehoux. p47phox-dependent NADPH oxidase regulates flow-induced vascular remodeling. Circ. Res. 97:533–540, 2005.PubMedCrossRefGoogle Scholar
  16. 16.
    Chatzizisis, Y. S., M. Jonas, A. U. Coskun, R. Beigel, B. V. Stone, C. Maynard, R. G. Gerrity, W. Daley, C. Rogers, E. R. Edelman, C. L. Feldman, and P. H. Stone. Prediction of the localization of high-risk coronary atherosclerotic plaques on the basis of low endothelial shear stress: an intravascular ultrasound and histopathology natural history study. Circulation 117:993–1002, 2008.PubMedCrossRefGoogle Scholar
  17. 17.
    Chien, S. Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am. J. Physiol. Heart Circ. Physiol. 292:H1209–H1224, 2007.PubMedCrossRefGoogle Scholar
  18. 18.
    Davies, P. F. Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75:519–560, 1995.PubMedGoogle Scholar
  19. 19.
    DePaola, N., P. F. Davies, W. F. Pritchard, Jr., L. Florez, N. Harbeck, and D. C. Polacek. Spatial and temporal regulation of gap junction connexin43 in vascular endothelial cells exposed to controlled disturbed flows in vitro. Proc. Natl Acad. Sci. USA 96:3154–3159, 1999.PubMedCrossRefGoogle Scholar
  20. 20.
    Dolan, J. M., H. Meng, S. Singh, R. Paluch, and J. Kolega. High fluid shear stress and spatial shear stress gradients affect endothelial proliferation, survival, and alignment. Ann. Biomed. Eng. 39:1620–1631, 2011.PubMedCrossRefGoogle Scholar
  21. 21.
    Dolan, J. M., F. J. Sim, H. Meng, and J. Kolega. Endothelial cells express a unique transcriptional profile under very high wall shear stress known to induce expansive arterial remodeling. Am. J. Physiol. Cell Physiol. 302:C1109–C1118, 2012.PubMedCrossRefGoogle Scholar
  22. 22.
    Dumont, O., L. Loufrani, and D. Henrion. Key role of the NO-pathway and matrix metalloprotease-9 in high blood flow-induced remodeling of rat resistance arteries. Arterioscler. Thromb. Vasc. Biol. 27:317–324, 2007.PubMedCrossRefGoogle Scholar
  23. 23.
    Eldawoody, H., H. Shimizu, N. Kimura, A. Saito, T. Nakayama, A. Takahashi, and T. Tominaga. Simplified experimental cerebral aneurysm model in rats: comprehensive evaluation of induced aneurysms and arterial changes in the circle of Willis. Brain Res. 1300:159–168, 2009.PubMedCrossRefGoogle Scholar
  24. 24.
    Frosen, J., R. Tulamo, A. Paetau, E. Laaksamo, M. Korja, A. Laakso, M. Niemela, and J. Hernesniemi. Saccular intracranial aneurysm: pathology and mechanisms. Acta Neuropathol. 123:773–786, 2012.PubMedCrossRefGoogle Scholar
  25. 25.
    Fujii, K., Y. Kobayashi, G. S. Mintz, H. Takebayashi, G. Dangas, I. Moussa, R. Mehran, A. J. Lansky, E. Kreps, M. Collins, A. Colombo, G. W. Stone, M. B. Leon, and J. W. Moses. Intravascular ultrasound assessment of ulcerated ruptured plaques: a comparison of culprit and nonculprit lesions of patients with acute coronary syndromes and lesions in patients without acute coronary syndromes. Circulation 108:2473–2478, 2003.PubMedCrossRefGoogle Scholar
  26. 26.
    Fukuda, S., N. Hashimoto, H. Naritomi, I. Nagata, K. Nozaki, S. Kondo, M. Kurino, and H. Kikuchi. Prevention of rat cerebral aneurysm formation by inhibition of nitric oxide synthase. Circulation 101:2532–2538, 2000.PubMedCrossRefGoogle Scholar
  27. 27.
    Gao, L., Y. Hoi, D. D. Swartz, J. Kolega, A. Siddiqui, and H. Meng. Nascent aneurysm formation at the basilar terminus induced by hemodynamics. Stroke 39:2085–2090, 2008.PubMedCrossRefGoogle Scholar
  28. 28.
    Gertz, S. D., and W. C. Roberts. Hemodynamic shear force in rupture of coronary arterial atherosclerotic plaques. Am. J. Cardiol. 66:1368–1372, 1990.PubMedCrossRefGoogle Scholar
  29. 29.
    Gibbons, G. H., and V. J. Dzau. The emerging concept of vascular remodeling. N. Engl. J. Med. 330:1431–1438, 1994.PubMedCrossRefGoogle Scholar
  30. 30.
    Gijsen, F. J., F. Mastik, J. A. Schaar, J. C. Schuurbiers, W. J. van der Giessen, P. J. de Feyter, P. W. Serruys, A. F. van der Steen, and J. J. Wentzel. High shear stress induces a strain increase in human coronary plaques over a 6-month period. EuroIntervention. 7:121–127, 2011.PubMedCrossRefGoogle Scholar
  31. 31.
    Gijsen, F. J., J. J. Wentzel, A. Thury, F. Mastik, J. A. Schaar, J. C. Schuurbiers, C. J. Slager, W. J. van der Giessen, P. J. de Feyter, A. F. van der Steen, and P. W. Serruys. Strain distribution over plaques in human coronary arteries relates to shear stress. Am. J. Physiol. Heart Circ. Physiol. 295:H1608–H1614, 2008.PubMedCrossRefGoogle Scholar
  32. 32.
    Glagov, S., E. Weisenberg, C. K. Zarins, R. Stankunavicius, and G. J. Kolettis. Compensatory enlargement of human atherosclerotic coronary arteries. N. Engl. J. Med. 316:1371–1375, 1987.PubMedCrossRefGoogle Scholar
  33. 33.
    Glagov, S., C. Zarins, D. P. Giddens, and D. N. Ku. Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch. Pathol. Lab. Med. 112:1018–1031, 1988.PubMedGoogle Scholar
  34. 34.
    Greve, J. M., A. S. Les, B. T. Tang, M. T. Draney Blomme, N. M. Wilson, R. L. Dalman, N. J. Pelc, and C. A. Taylor. Allometric scaling of wall shear stress from mice to humans: quantification using cine phase-contrast MRI and computational fluid dynamics. Am. J. Physiol. Heart Circ. Physiol. 291:H1700–H1708, 2006.PubMedCrossRefGoogle Scholar
  35. 35.
    Groen, H. C., F. J. Gijsen, A. van der Lugt, M. S. Ferguson, T. S. Hatsukami, A. F. van der Steen, C. Yuan, and J. J. Wentzel. Plaque rupture in the carotid artery is localized at the high shear stress region: a case report. Stroke 38:2379–2381, 2007.PubMedCrossRefGoogle Scholar
  36. 36.
    Guzman, R. J., K. Abe, and C. K. Zarins. Flow-induced arterial enlargement is inhibited by suppression of nitric oxide synthase activity in vivo. Surgery 122:273–279, 1997; discussion 279–280.Google Scholar
  37. 37.
    Han, H. C. Twisted blood vessels: symptoms, etiology and biomechanical mechanisms. J. Vasc. Res. 49:185–197, 2012.PubMedCrossRefGoogle Scholar
  38. 38.
    Hashimoto, N., H. Handa, and F. Hazama. Experimentally induced cerebral aneurysms in rats. Surg. Neurol. 10:3–8, 1978.PubMedGoogle Scholar
  39. 39.
    Hashimoto, N., H. Handa, I. Nagata, and F. Hazama. Experimentally induced cerebral aneurysms in rats: Part V. Relation of hemodynamics in the circle of Willis to formation of aneurysms. Surg. Neurol. 13:41–45, 1980.PubMedGoogle Scholar
  40. 40.
    Hashimoto, T., H. Meng, and W. L. Young. Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol. Res. 28:372–380, 2006.PubMedCrossRefGoogle Scholar
  41. 41.
    Hazama, F., H. Kataoka, E. Yamada, K. Kayembe, N. Hashimoto, M. Kojima, and C. Kim. Early changes of experimentally induced cerebral aneurysms in rats. Light-microscopic study. Am. J. Pathol. 124:399–404, 1986.PubMedGoogle Scholar
  42. 42.
    Hoi, Y., L. Gao, M. Tremmel, R. A. Paluch, A. H. Siddiqui, H. Meng, and J. Mocco. In vivo assessment of rapid cerebrovascular morphological adaptation following acute blood flow increase. J. Neurosurg. 109:1141–1147, 2008.PubMedCrossRefGoogle Scholar
  43. 43.
    Hsieh, H. J., N. Q. Li, and J. A. Frangos. Shear-induced platelet-derived growth factor gene expression in human endothelial cells is mediated by protein kinase C. J. Cell. Physiol. 150:552–558, 1992.PubMedCrossRefGoogle Scholar
  44. 44.
    Hyun, S., C. Kleinstreuer, and J. P. Archie, Jr. Hemodynamics analyses of arterial expansions with implications to thrombosis and restenosis. Med. Eng. Phys. 22:13–27, 2000.PubMedCrossRefGoogle Scholar
  45. 45.
    Ishibashi, A., Y. Yokokura, K. Kojima, and T. Abe. Acute obstructive hydrocephalus due to an unruptured basilar bifurcation aneurysm associated with bilateral internal carotid occlusion—a case report. Kurume Med. J. 40:21–25, 1993.PubMedCrossRefGoogle Scholar
  46. 46.
    Jamous, M. A., S. Nagahiro, K. T. Kitazato, J. Satomi, and K. Satoh. Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part I: experimental study of the effect of oophorectomy in rats. J. Neurosurg. 103:1046–1051, 2005.PubMedCrossRefGoogle Scholar
  47. 47.
    Jamous, M. A., S. Nagahiro, K. T. Kitazato, T. Tamura, H. A. Aziz, M. Shono, and K. Satoh. Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats. J. Neurosurg. 107:405–411, 2007.PubMedCrossRefGoogle Scholar
  48. 48.
    Jesty, J., W. Yin, P. Perrotta, and D. Bluestein. Platelet activation in a circulating flow loop: combined effects of shear stress and exposure time. Platelets 14:143–149, 2003.PubMedCrossRefGoogle Scholar
  49. 49.
    Jou, L. D., R. van Tyen, S. A. Berger, and D. Saloner. Calculation of the magnetization distribution for fluid flow in curved vessels. Magn. Reson. Med. 35:577–584, 1996.PubMedCrossRefGoogle Scholar
  50. 50.
    Juvela, S. Natural history of unruptured intracranial aneurysms: risks for aneurysm formation, growth, and rupture. Acta Neurochir. Suppl. 82:27–30, 2002.PubMedGoogle Scholar
  51. 51.
    Kamiya, A., R. Bukhari, and T. Togawa. Adaptive regulation of wall shear stress optimizing vascular tree function. Bull. Math. Biol. 46:127–137, 1984.PubMedGoogle Scholar
  52. 52.
    Kamiya, A., and T. Togawa. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am. J. Physiol. 239:H14–H21, 1980.PubMedGoogle Scholar
  53. 53.
    Karwowski, J. K., A. Markezich, J. Whitson, T. A. Abbruzzese, C. K. Zarins, and R. L. Dalman. Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113,456. J. Surg. Res. 87:122–129, 1999.PubMedCrossRefGoogle Scholar
  54. 54.
    Kataoka, K., M. Taneda, T. Asai, A. Kinoshita, M. Ito, and R. Kuroda. Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 30:1396–1401, 1999.PubMedCrossRefGoogle Scholar
  55. 55.
    Kojima, M., H. Handa, N. Hashimoto, C. Kim, and F. Hazama. Early changes of experimentally induced cerebral aneurysms in rats: scanning electron microscopic study. Stroke 17:835–841, 1986.PubMedCrossRefGoogle Scholar
  56. 56.
    Kolega, J., L. Gao, M. Mandelbaum, J. Mocco, A. H. Siddiqui, S. K. Natarajan, and H. Meng. Cellular and molecular responses of the basilar terminus to hemodynamics during intracranial aneurysm initiation in a rabbit model. J. Vasc. Res. 48:429–442, 2011.PubMedCrossRefGoogle Scholar
  57. 57.
    Koskinas, K. C., C. L. Feldman, Y. S. Chatzizisis, A. U. Coskun, M. Jonas, C. Maynard, A. B. Baker, M. I. Papafaklis, E. R. Edelman, and P. H. Stone. Natural history of experimental coronary atherosclerosis and vascular remodeling in relation to endothelial shear stress: a serial, in vivo intravascular ultrasound study. Circulation 121:2092–2101, 2010.PubMedCrossRefGoogle Scholar
  58. 58.
    Kulcsar, Z., A. Ugron, M. Marosfoi, Z. Berentei, G. Paal, and I. Szikora. Hemodynamics of cerebral aneurysm initiation: the role of wall shear stress and spatial wall shear stress gradient. AJNR Am. J. Neuroradiol. 32:587–594, 2011.PubMedCrossRefGoogle Scholar
  59. 59.
    Kwak, B. R., P. Silacci, N. Stergiopulos, D. Hayoz, and P. Meda. Shear stress and cyclic circumferential stretch, but not pressure, alter connexin43 expression in endothelial cells. Cell Commun. Adhes. 12:261–270, 2005.PubMedCrossRefGoogle Scholar
  60. 60.
    LaBarbera, M. Principles of design of fluid transport systems in zoology. Science 249:992–1000, 1990.PubMedCrossRefGoogle Scholar
  61. 61.
    LaMack, J. A., and M. H. Friedman. Individual and combined effects of shear stress magnitude and spatial gradient on endothelial cell gene expression. Am. J. Physiol. Heart Circ. Physiol. 293:H2853–H2859, 2007.PubMedCrossRefGoogle Scholar
  62. 62.
    Langille, B. L., and F. O’Donnell. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 231:405–407, 1986.PubMedCrossRefGoogle Scholar
  63. 63.
    Leach, J. R., V. L. Rayz, B. Soares, M. Wintermark, M. R. Mofrad, and D. Saloner. Carotid atheroma rupture observed in vivo and FSI-predicted stress distribution based on pre-rupture imaging. Ann. Biomed. Eng. 38:2748–2765, 2010.PubMedCrossRefGoogle Scholar
  64. 64.
    Lehman, R. M., G. K. Owens, N. F. Kassell, and K. Hongo. Mechanism of enlargement of major cerebral collateral arteries in rabbits. Stroke 22:499–504, 1991.PubMedCrossRefGoogle Scholar
  65. 65.
    Lehoux, S., Y. Castier, and A. Tedgui. Molecular mechanisms of the vascular responses to haemodynamic forces. J. Intern. Med. 259:381–392, 2006.PubMedCrossRefGoogle Scholar
  66. 66.
    Lehoux, S., F. Tronc, and A. Tedgui. Mechanisms of blood flow-induced vascular enlargement. Biorheology. 39:319–324, 2002.PubMedGoogle Scholar
  67. 67.
    Levkau, B., R. D. Kenagy, A. Karsan, B. Weitkamp, A. W. Clowes, R. Ross, and E. W. Raines. Activation of metalloproteinases and their association with integrins: an auxiliary apoptotic pathway in human endothelial cells. Cell Death Differ. 9:1360–1367, 2002.PubMedCrossRefGoogle Scholar
  68. 68.
    Li, Z. Y., V. Taviani, T. Tang, U. Sadat, V. Young, A. Patterson, M. Graves, and J. H. Gillard. The mechanical triggers of plaque rupture: shear stress vs pressure gradient. Br. J. Radiol. 82(Spec No. 1):S39–S45, 2009.Google Scholar
  69. 69.
    Lindekleiv, H. M., K. Valen-Sendstad, M. K. Morgan, K. A. Mardal, K. Faulder, J. H. Magnus, K. Waterloo, B. Romner, and T. Ingebrigtsen. Sex differences in intracranial arterial bifurcations. Gend. Med. 7:149–155, 2010.PubMedCrossRefGoogle Scholar
  70. 70.
    Lovett, J. K., and P. M. Rothwell. Site of carotid plaque ulceration in relation to direction of blood flow: an angiographic and pathological study. Cerebrovasc. Dis. 16:369–375, 2003.PubMedCrossRefGoogle Scholar
  71. 71.
    Malek, A. M., S. L. Alper, and S. Izumo. Hemodynamic shear stress and its role in atherosclerosis. JAMA 282:2035–2042, 1999.PubMedCrossRefGoogle Scholar
  72. 72.
    Malek, A. M., G. H. Gibbons, V. J. Dzau, and S. Izumo. Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor B chain in vascular endothelium. J. Clin. Invest. 92:2013–2021, 1993.PubMedCrossRefGoogle Scholar
  73. 73.
    Masuda, H., Y. J. Zhuang, T. M. Singh, K. Kawamura, M. Murakami, C. K. Zarins, and S. Glagov. Adaptive remodeling of internal elastic lamina and endothelial lining during flow-induced arterial enlargement. Arterioscler. Thromb. Vasc. Biol. 19:2298–2307, 1999.PubMedCrossRefGoogle Scholar
  74. 74.
    Meng, H., E. Metaxa, L. Gao, N. Liaw, S. K. Natarajan, D. D. Swartz, A. H. Siddiqui, J. Kolega, and J. Mocco. Progressive aneurysm development following hemodynamic insult. J. Neurosurg. 114:1095–1103, 2011.PubMedCrossRefGoogle Scholar
  75. 75.
    Meng, H., D. D. Swartz, Z. Wang, Y. Hoi, J. Kolega, E. M. Metaxa, M. P. Szymanski, J. Yamamoto, E. Sauvageau, and E. I. Levy. A model system for mapping vascular responses to complex hemodynamics at arterial bifurcations in vivo. Neurosurgery. 59:1094–1100, 2006; discussion 1100–1101.Google Scholar
  76. 76.
    Meng, H., Z. Wang, Y. Hoi, L. Gao, E. Metaxa, D. D. Swartz, and J. Kolega. Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation. Stroke 38:1924–1931, 2007.PubMedCrossRefGoogle Scholar
  77. 77.
    Meng, H., J. Xiang, and N. Liaw. The role of hemodynamics in intracranial aneurysm initiation. Int. Rev. Thrombosis. 7:40–57, 2012.Google Scholar
  78. 78.
    Metaxa, E., H. Meng, S. R. Kaluvala, M. P. Szymanski, R. A. Paluch, and J. Kolega. Nitric oxide-dependent stimulation of endothelial cell proliferation by sustained high flow. Am. J. Physiol. Heart Circ. Physiol. 295:H736–H742, 2008.PubMedCrossRefGoogle Scholar
  79. 79.
    Metaxa, E., M. Tremmel, S. K. Natarajan, J. Xiang, R. A. Paluch, M. Mandelbaum, A. H. Siddiqui, J. Kolega, J. Mocco, and H. Meng. Characterization of critical hemodynamics contributing to aneurysmal remodeling at the basilar terminus in a rabbit model. Stroke 41:1774–1782, 2010.PubMedCrossRefGoogle Scholar
  80. 80.
    Mintz, G. S., K. M. Kent, A. D. Pichard, L. F. Satler, J. J. Popma, and M. B. Leon. Contribution of inadequate arterial remodeling to the development of focal coronary artery stenoses. An intravascular ultrasound study. Circulation. 95:1791–1798, 1997.PubMedCrossRefGoogle Scholar
  81. 81.
    Moore, Jr., J. E., E. Burki, A. Suciu, S. Zhao, M. Burnier, H. R. Brunner, and J. J. Meister. A device for subjecting vascular endothelial cells to both fluid shear stress and circumferential cyclic stretch. Ann. Biomed. Eng. 22:416–422, 1994.PubMedCrossRefGoogle Scholar
  82. 82.
    Moriwaki, T., Y. Takagi, N. Sadamasa, T. Aoki, K. Nozaki, and N. Hashimoto. Impaired progression of cerebral aneurysms in interleukin-1beta-deficient mice. Stroke 37:900–905, 2006.PubMedCrossRefGoogle Scholar
  83. 83.
    Murray, C. D. The physiological principle of minimum work: I. The vascular system and the cost of blood volume. Proc. Natl Acad. Sci. USA 12:207–214, 1926.PubMedCrossRefGoogle Scholar
  84. 84.
    Nagata, I., H. Handa, N. Hashimoto, and F. Hazama. Experimentally induced cerebral aneurysms in rats: Part VI. Hypertension. Surg. Neurol. 14:477–479, 1980.PubMedGoogle Scholar
  85. 85.
    Nakatani, H., N. Hashimoto, Y. Kang, N. Yamazoe, H. Kikuchi, S. Yamaguchi, and H. Niimi. Cerebral blood flow patterns at major vessel bifurcations and aneurysms in rats. J. Neurosurg. 74:258–262, 1991.PubMedCrossRefGoogle Scholar
  86. 86.
    Neelamegham, S., A. D. Taylor, A. R. Burns, C. W. Smith, and S. I. Simon. Hydrodynamic shear shows distinct roles for LFA-1 and Mac-1 in neutrophil adhesion to intercellular adhesion molecule-1. Blood 92:1626–1638, 1998.PubMedGoogle Scholar
  87. 87.
    Nuki, Y., M. M. Matsumoto, E. Tsang, W. L. Young, N. van Rooijen, C. Kurihara, and T. Hashimoto. Roles of macrophages in flow-induced outward vascular remodeling. J. Cereb. Blood Flow Metab. 29:495–503, 2009.PubMedCrossRefGoogle Scholar
  88. 88.
    Park, J. B., F. Charbonneau, and E. L. Schiffrin. Correlation of endothelial function in large and small arteries in human essential hypertension. J. Hypertens. 19:415–420, 2001.PubMedCrossRefGoogle Scholar
  89. 89.
    Rajagopalan, S., X. P. Meng, S. Ramasamy, D. G. Harrison, and Z. S. Galis. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J. Clin. Invest. 98:2572–2579, 1996.PubMedCrossRefGoogle Scholar
  90. 90.
    Rinkel, G. J., M. Djibuti, A. Algra, and J. van Gijn. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 29:251–256, 1998.PubMedCrossRefGoogle Scholar
  91. 91.
    Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340:115–126, 1999.PubMedCrossRefGoogle Scholar
  92. 92.
    Sakamoto, N., N. Saito, X. Han, T. Ohashi, and M. Sato. Effect of spatial gradient in fluid shear stress on morphological changes in endothelial cells in response to flow. Biochem. Biophys. Res. Commun. 395:264–269, 2010.PubMedCrossRefGoogle Scholar
  93. 93.
    Samady, H., P. Eshtehardi, M. C. McDaniel, J. Suo, S. S. Dhawan, C. Maynard, L. H. Timmins, A. A. Quyyumi, and D. P. Giddens. Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease. Circulation 124:779–788, 2011.PubMedCrossRefGoogle Scholar
  94. 94.
    Schiffrin, E. L., J. B. Park, H. D. Intengan, and R. M. Touyz. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation 101:1653–1659, 2000.PubMedCrossRefGoogle Scholar
  95. 95.
    Schirmer, C. M., and A. M. Malek. Computational fluid dynamic characterization of carotid bifurcation stenosis in patient-based geometries. Brain Behav. 2:42–52, 2012.PubMedCrossRefGoogle Scholar
  96. 96.
    Schirmer, C. M., and A. M. Malek. Wall shear stress gradient analysis within an idealized stenosis using non-Newtonian flow. Neurosurgery 61:853–863, 2007; discussion 863–864.Google Scholar
  97. 97.
    Schoenhagen, P., K. M. Ziada, S. R. Kapadia, T. D. Crowe, S. E. Nissen, and E. M. Tuzcu. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes : an intravascular ultrasound study. Circulation 101:598–603, 2000.PubMedCrossRefGoogle Scholar
  98. 98.
    Sho, E., M. Komatsu, M. Sho, H. Nanjo, T. M. Singh, C. Xu, H. Masuda, and C. K. Zarins. High flow drives vascular endothelial cell proliferation during flow-induced arterial remodeling associated with the expression of vascular endothelial growth factor. Exp. Mol. Pathol. 75:1–11, 2003.PubMedCrossRefGoogle Scholar
  99. 99.
    Sho, E., M. Sho, T. M. Singh, H. Nanjo, M. Komatsu, C. Xu, H. Masuda, and C. K. Zarins. Arterial enlargement in response to high flow requires early expression of matrix metalloproteinases to degrade extracellular matrix. Exp. Mol. Pathol. 73:142–153, 2002.PubMedCrossRefGoogle Scholar
  100. 100.
    Shumacker, Jr., H. B. Aneurysm development and degenerative changes in dilated artery proximal to arteriovenous fistula. Surg. Gynecol. Obstet. 130:636–640, 1970.PubMedGoogle Scholar
  101. 101.
    Singh, T. M., K. Y. Abe, T. Sasaki, Y. J. Zhuang, H. Masuda, and C. K. Zarins. Basic fibroblast growth factor expression precedes flow-induced arterial enlargement. J. Surg. Res. 77:165–173, 1998.PubMedCrossRefGoogle Scholar
  102. 102.
    Slager, C. J., J. J. Wentzel, F. J. Gijsen, J. C. Schuurbiers, A. C. van der Wal, A. F. van der Steen, and P. W. Serruys. The role of shear stress in the generation of rupture-prone vulnerable plaques. Nat. Clin. Pract. Cardiovasc. Med. 2:401–407, 2005.PubMedCrossRefGoogle Scholar
  103. 103.
    Stehbens, W. E. Aneurysms and anatomical variation of cerebral arteries. Arch. Pathol. 75:45–64, 1963.PubMedGoogle Scholar
  104. 104.
    Stone, P. H., A. U. Coskun, S. Kinlay, M. E. Clark, M. Sonka, A. Wahle, O. J. Ilegbusi, Y. Yeghiazarians, J. J. Popma, J. Orav, R. E. Kuntz, and C. L. Feldman. Effect of endothelial shear stress on the progression of coronary artery disease, vascular remodeling, and in-stent restenosis in humans: in vivo 6-month follow-up study. Circulation 108:438–444, 2003.PubMedCrossRefGoogle Scholar
  105. 105.
    Szymanski, M. P., E. Metaxa, H. Meng, and J. Kolega. Endothelial cell layer subjected to impinging flow mimicking the apex of an arterial bifurcation. Ann. Biomed. Eng. 36:1681–1689, 2008.PubMedCrossRefGoogle Scholar
  106. 106.
    Tada, Y., K. T. Kitazato, K. Yagi, K. Shimada, N. Matsushita, T. Kinouchi, Y. Kanematsu, J. Satomi, T. Kageji, and S. Nagahiro. Statins promote the growth of experimentally induced cerebral aneurysms in estrogen-deficient rats. Stroke 42:2286–2293, 2011.PubMedCrossRefGoogle Scholar
  107. 107.
    Tada, Y., K. Yagi, K. T. Kitazato, T. Tamura, T. Kinouchi, K. Shimada, N. Matsushita, N. Nakajima, J. Satomi, T. Kageji, and S. Nagahiro. Reduction of endothelial tight junction proteins is related to cerebral aneurysm formation in rats. J. Hypertens. 28:1883–1891, 2010.PubMedCrossRefGoogle Scholar
  108. 108.
    Tanweer, O., E. Metaxa, N. Liaw, S. Sternberg, A. Siddiqui, J. Kolega, and H. Meng. Inhibition of stretch-activated ion channels on endothelial cells disrupts nitric oxide-mediated arterial outward remodeling. J. Biorheol. 24:77–83, 2011.CrossRefGoogle Scholar
  109. 109.
    Teng, Z., G. Canton, C. Yuan, M. Ferguson, C. Yang, X. Huang, J. Zheng, P. K. Woodard, and D. Tang. 3D critical plaque wall stress is a better predictor of carotid plaque rupture sites than flow shear stress: an in vivo MRI-based 3D FSI study. J. Biomech. Eng. 132:031007, 2010.PubMedCrossRefGoogle Scholar
  110. 110.
    Thi, M. M., J. M. Tarbell, S. Weinbaum, and D. C. Spray. The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: a “bumper-car” model. Proc. Natl Acad. Sci. USA 101:16483–16488, 2004.PubMedCrossRefGoogle Scholar
  111. 111.
    Tohda, K., H. Masuda, K. Kawamura, and T. Shozawa. Difference in dilatation between endothelium-preserved and -desquamated segments in the flow-loaded rat common carotid artery. Arterioscler. Thromb. 12:519–528, 1992.PubMedCrossRefGoogle Scholar
  112. 112.
    Torii, R., N. B. Wood, N. Hadjiloizou, A. W. Dowsey, A. R. Wright, A. D. Hughes, J. Davies, D. P. Francis, J. Mayet, G. Z. Yang, S. A. Thom, and X. Y. Xu. Stress phase angle depicts differences in coronary artery hemodynamics due to changes in flow and geometry after percutaneous coronary intervention. Am. J. Physiol. Heart Circ. Physiol. 296:H765–H776, 2009.PubMedCrossRefGoogle Scholar
  113. 113.
    Tremmel, M., J. Xiang, S. K. Natarajan, L. N. Hopkins, A. H. Siddiqui, E. I. Levy, and H. Meng. Alteration of intra-aneurysmal hemodynamics for flow diversion using enterprise and vision stents. World Neurosurg. 74:306–315, 2010.PubMedCrossRefGoogle Scholar
  114. 114.
    Tronc, F., Z. Mallat, S. Lehoux, M. Wassef, B. Esposito, and A. Tedgui. Role of matrix metalloproteinases in blood flow-induced arterial enlargement: interaction with NO. Arterioscler. Thromb. Vasc. Biol. 20:E120–E126, 2000.PubMedCrossRefGoogle Scholar
  115. 115.
    Tronc, F., M. Wassef, B. Esposito, D. Henrion, S. Glagov, and A. Tedgui. Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler. Thromb. Vasc. Biol. 16:1256–1262, 1996.PubMedCrossRefGoogle Scholar
  116. 116.
    Tuttle, J. L., R. D. Nachreiner, A. S. Bhuller, K. W. Condict, B. A. Connors, B. P. Herring, M. C. Dalsing, and J. L. Unthank. Shear level influences resistance artery remodeling: wall dimensions, cell density, and eNOS expression. Am. J. Physiol. Heart Circ. Physiol. 281:H1380–H1389, 2001.PubMedGoogle Scholar
  117. 117.
    Tzima, E., M. Irani-Tehrani, W. B. Kiosses, E. Dejana, D. A. Schultz, B. Engelhardt, G. Cao, H. DeLisser, and M. A. Schwartz. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437:426–431, 2005.PubMedCrossRefGoogle Scholar
  118. 118.
    van Everdingen, K. J., C. J. Klijn, L. J. Kappelle, W. P. Mali, and J. van der Grond. MRA flow quantification in patients with a symptomatic internal carotid artery occlusion. The Dutch EC-IC Bypass Study Group. Stroke 28:1595–1600, 1997.PubMedCrossRefGoogle Scholar
  119. 119.
    Van Remmen, H., M. D. Williams, Z. Guo, L. Estlack, H. Yang, E. J. Carlson, C. J. Epstein, T. T. Huang, and A. Richardson. Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis. Am. J. Physiol. Heart Circ. Physiol. 281:H1422–H1432, 2001.PubMedGoogle Scholar
  120. 120.
    Varnava, A. M., P. G. Mills, and M. J. Davies. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 105:939–943, 2002.PubMedCrossRefGoogle Scholar
  121. 121.
    Vega, C., J. V. Kwoon, and S. D. Lavine. Intracranial aneurysms: current evidence and clinical practice. Am. Fam. Physician 66:601–608, 2002.PubMedGoogle Scholar
  122. 122.
    Waga, S., M. Okada, and T. Kojima. Saccular aneurysm associated with absence of the left cervical carotid arteries. Neurosurgery. 3:208–212, 1978.PubMedCrossRefGoogle Scholar
  123. 123.
    Wang, Z., J. Kolega, Y. Hoi, L. Gao, D. D. Swartz, E. I. Levy, J. Mocco, and H. Meng. Molecular alterations associated with aneurysmal remodeling are localized in the high hemodynamic stress region of a created carotid bifurcation. Neurosurgery 65:169–177, 2009; discussion 177–178.Google Scholar
  124. 124.
    Weinberg, P. D., and C. Ross Ethier. Twenty-fold difference in hemodynamic wall shear stress between murine and human aortas. J. Biomech. 40:1594–1598, 2007.PubMedCrossRefGoogle Scholar
  125. 125.
    Wentzel, J. J., Y. S. Chatzizisis, F. J. Gijsen, G. D. Giannoglou, C. L. Feldman, and P. H. Stone. Endothelial shear stress in the evolution of coronary atherosclerotic plaque and vascular remodeling: current understanding and remaining questions. Cardiovasc. Res. 96(2):234–243, 2012.PubMedCrossRefGoogle Scholar
  126. 126.
    White, S. J., E. M. Hayes, S. Lehoux, J. Y. Jeremy, A. J. Horrevoets, and A. C. Newby. Characterization of the differential response of endothelial cells exposed to normal and elevated laminar shear stress. J. Cell. Physiol. 226:2841–2848, 2011.PubMedCrossRefGoogle Scholar
  127. 127.
    Yong-Zhong, G., and H. A. van Alphen. Pathogenesis and histopathology of saccular aneurysms: review of the literature. Neurol. Res. 12:249–255, 1990.PubMedGoogle Scholar
  128. 128.
    Zarins, C. K., D. P. Giddens, B. K. Bharadvaj, V. S. Sottiurai, R. F. Mabon, and S. Glagov. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ. Res. 53:502–514, 1983.PubMedCrossRefGoogle Scholar
  129. 129.
    Zarins, C. K., M. A. Zatina, D. P. Giddens, D. N. Ku, and S. Glagov. Shear stress regulation of artery lumen diameter in experimental atherogenesis. J. Vasc. Surg. 5:413–420, 1987.PubMedGoogle Scholar
  130. 130.
    Zhao, S., A. Suciu, T. Ziegler, J. E. Moore, Jr., E. Burki, J. J. Meister, and H. R. Brunner. Synergistic effects of fluid shear stress and cyclic circumferential stretch on vascular endothelial cell morphology and cytoskeleton. Arterioscler. Thromb. Vasc. Biol. 15:1781–1786, 1995.PubMedCrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2012

Authors and Affiliations

  • Jennifer M. Dolan
    • 1
    • 3
    • 4
  • John Kolega
    • 1
    • 3
    • 4
  • Hui Meng
    • 1
    • 2
    • 3
    • 5
  1. 1.Toshiba Stroke and Vascular Research CenterClinical and Translational Research Center of the University at Buffalo, State University of New YorkBuffaloUSA
  2. 2.Department of Mechanical and Aerospace EngineeringUniversity at Buffalo, State University of New YorkBuffaloUSA
  3. 3.Neuroscience ProgramUniversity at Buffalo, State University of New YorkBuffaloUSA
  4. 4.Department of Pathology and Anatomical SciencesUniversity at Buffalo, State University of New YorkBuffaloUSA
  5. 5.Department of NeurosurgeryUniversity at Buffalo, State University of New YorkBuffaloUSA

Personalised recommendations