Abstract
Little is known about endothelial responses to the impinging flow hemodynamics that occur at arterial bifurcation apices, where intracranial aneurysms usually form. Such hemodynamic environments are characterized by high wall shear stress (WSS >40 dynes/cm2) and high wall shear stress gradients (WSSG >300 dynes/cm3). In this study, confluent bovine aortic endothelial cells were exposed to impinging flow in a T-shaped chamber designed to mimic a bifurcation. After 24–72 h under flow, cells around the stagnation point maintained polygonal shapes but cell density was reduced, whereas cells in adjacent downstream regions exposed to very high WSS and WSSG were elongated, aligned parallel to flow, and at higher density. Such behavior was not blocked by inhibiting proliferation, indicating that cells migrated downstream from the stagnation point in response to impinging flow. Furthermore, although the area of highest cell density moved downstream and away from the impingement point over time, it never moved beyond the WSS maximum. The accumulation of cells upstream of maximal WSS and downstream of maximal WSSG suggests that positive WSSG is responsible for the observed migration. These results demonstrate a unique endothelial response to aneurysm-promoting flow environments at bifurcation apices.
Similar content being viewed by others
References
Abramoff M. D., P. J. Magelhaes, S. J. Ram Image processing with imageJ. Biophoton. Int. 11: 36–42, 2004
Akahane T., M. Akahane, A. Shah, C. M. Connor, U. P. Thorgeirsson TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Exp. Cell Res. 301: 158–167, 2004. doi:10.1016/j.yexcr.2004.08.002
Akimoto S., M. Mitsumata, T. Sasaguri, Y. Yoshida Laminar shear stress inhibits vascular endothelial cell proliferation by inducing cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1). Circ. Res. 86: 185–190, 2000
Akinaga S., K. Nomura, K. Gomi, M. Okabe Enhancement of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C. Cancer Chemother. Pharmacol. 32: 183–189, 1993. doi:10.1007/BF00685833
Albuquerque M. L., C. M. Waters, U. Savla, H. W. Schnaper, A. S. Flozak Shear stress enhances human endothelial cell wound closure in vitro. Am. J. Physiol. 279: H293–302, 2000
Caro C. G., J. M. Fitz-Gerald, 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
Chen B. P., Y. S. Li, Y. Zhao, K. D. Chen, S. Li, J. Lao, S. Yuan, J. Y. Shyy, S. Chien DNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress. Physiol. Genomics 7: 55–63, 2001. doi:10.1006/geno.2001.6511
Chien S. Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am. J. Physiol. Heart Circ. Physiol. 292: H1209–1224, 2007. doi:10.1152/ajpheart.01047.2006
Chien S., S. Li, Y. J. Shyy Effects of mechanical forces on signal transduction and gene expression in endothelial cells. Hypertension 31: 162–169, 1998
Chiu J. J., C. N. Chen, P. L. Lee, C. T. Yang, H. S. Chuang, S. Chien, S. Usami Analysis of the effect of disturbed flow on monocytic adhesion to endothelial cells. J. Biomech. 36: 1883–1895, 2003. doi:10.1016/S0021-9290(03)00210-0
Chiu J. J., D. L. Wang, S. Chien, R. Skalak, S. Usami Effects of disturbed flow on endothelial cells. J. Biomech. Eng. 120: 2–8, 1998. doi:10.1115/1.2834303
Davies P. F. Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75: 519–560, 1995
DePaola N., P. F. Davies, W. F. Pritchard Jr., L. Florez, N. Harbeck, 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. doi:10.1073/pnas.96.6.3154
DePaola N., M. A. Gimbrone Jr., P. F. Davies, C. F. Dewey Jr. Vascular endothelium responds to fluid shear stress gradients. Arterioscler. Thromb. 12: 1254–1257, 1992
Gao L., Y. Hoi, D. D. Swartz, J. Kolega, A. Siddiqui, H. Meng (2008) Nascent aneurysm formation at basilar terminus induced by hemodynamics. Stroke 39:2085–2090
Glagov S., C. Zarins, D. P. Giddens, D. N. Ku Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch. Pathol. Lab. Med. 112: 1018–1031, 1988
Hashimoto N., H. Handa, I. Nagata, F. Hazama 1980 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
Himburg H. A., D. M. Grzybowski, A. L. Hazel, J. A. LaMack, X. M. Li, M. H. Friedman Spatial comparison between wall shear stress measures and porcine arterial endothelial permeability. Am. J. Physiol. Heart Circ. Physiol. 286: H1916–1922, 2004. doi:10.1152/ajpheart.00897.2003
Hoi Y., H. Meng, S. H. Woodward, B. R. Bendok, R. A. Hanel, L. R. Guterman, L. N. Hopkins Effects of arterial geometry on aneurysm growth: three-dimensional computational fluid dynamics study. J. Neurosurg. 101: 676–681, 2004
Hoi Y., S. H. Woodward, M. Kim, D. B. Taulbee, H. Meng Validation of CFD simulations of cerebral aneurysms with implication of geometric variations. J. Biomech. Eng. 128: 844–851, 2006. doi:10.1115/1.2354209
Hsu P. P., S. Li, Y. S. Li, S. Usami, A. Ratcliffe, X. Wang, S. Chien Effects of flow patterns on endothelial cell migration into a zone of mechanical denudation. Biochem. Biophys. Res. Commun. 285: 751–759, 2001. doi:10.1006/bbrc.2001.5221
Krex D., H. K. Schackert, G. Schackert Genesis of cerebral aneurysms – an update. Acta Neurochir. (Wien) 143: 429–448; 2001; discussion 448–429
LaMack J. A., 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: H2853–2859, 2007. doi:10.1152/ajpheart.00244.2007
LaMack J. A., H. A. Himburg, X. M. Li, M. H. Friedman Interaction of wall shear stress magnitude and gradient in the prediction of arterial macromolecular permeability. Ann. Biomed. Eng. 33: 457–464, 2005. doi:10.1007/s10439-005-2500-9
Meng H., D. D. Swartz, Z. Wang, Y. Hoi, J. Kolega, E. M. Metaxa, M. P. Szymanski, J. Yamamoto, E. Sauvageau, E. I. Levy A model system for mapping vascular responses to complex hemodynamics at arterial bifurcations in vivo. Neurosurgery 59: 1094–1100; 2006, discussion 1100–1091
Meng H., Z. Wang, Y. Hoi, L. Gao, E. Metaxa, D. D. Swartz, J. Kolega Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation. Stroke 38: 1924–1931, 2007. doi:10.1161/STROKEAHA.106.481234
Sho E., M. Komatsu, M. Sho, H. Nanjo, T. M. Singh, C. Xu, H. Masuda, 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. doi:10.1016/S0014-4800(03)00032-7
Shojima M., M. Oshima, K. Takagi, R. Torii, M. Hayakawa, K. Katada, A. Morita, T. Kirino Magnitude and role of wall shear stress on cerebral aneurysm: computational fluid dynamic study of 20 middle cerebral artery aneurysms. Stroke 35: 2500–2505, 2004. doi:10.1161/01.STR.0000144648.89172.0f
Stehbens W. E. Histopathology of cerebral aneurysms. Arch Neurol. 8: 272–285, 1963
Tardy Y., N. Resnick, T. Nagel, M. A. Gimbrone Jr., C. F. Dewey Jr. Shear stress gradients remodel endothelial monolayers in vitro via a cell proliferation-migration-loss cycle. Arterioscler. Thromb. Vasc. Biol. 17: 3102–3106, 1997
Tzima E., M. Irani-Tehrani, W. B. Kiosses, E. Dejana, D. A. Schultz, B. Engelhardt, G. Cao, H. DeLisser, M. A. Schwartz A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature. 437: 426–431, 2005. doi:10.1038/nature03952
Wechezak A. R., D. E. Coan, R. F. Viggers, L. R. Sauvage Dextran increases survival of subconfluent endothelial cells exposed to shear stress. Am. J. Physiol. 264: H520–525, 1993
White C. R., M. Haidekker, X. Bao, J. A. Frangos Temporal gradients in shear, but not spatial gradients, stimulate endothelial cell proliferation. Circulation 103: 2508–2513, 2001
Wright H. P. Endothelial mitosis around aortic branches in normal guinea pigs. Nature 220: 78–79, 1968. doi:10.1038/220078a0
Zarins C. K., D. P. Giddens, B. K. Bharadvaj, V. S. Sottiurai, R. F. Mabon, S. Glagov Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ. Res. 53: 502–514, 1983
Acknowledgments
We thank Yiemeng Hoi for CFD simulations, Daniel D. Swartz, Zhijie Wang, and Jennifer Dolan for critical suggestions to this study, and Scott W. Woodward for technical assistance in the flow chamber design. This work was supported by the NIH under Grant NS047242, NSF under Grant BES-0302389, and by the Cummings Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Szymanski, M.P., Metaxa, E., Meng, H. et al. Endothelial Cell Layer Subjected to Impinging Flow Mimicking the Apex of an Arterial Bifurcation. Ann Biomed Eng 36, 1681–1689 (2008). https://doi.org/10.1007/s10439-008-9540-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-008-9540-x