Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Cell Biol. 169 (1): 191-202

Copyright © 2005 by the Rockefeller University Press.


Article

The subendothelial extracellular matrix modulates NF-{kappa}B activation by flow

a potential role in atherosclerosis

A. Wayne Orr3, John M. Sanders3, Melissa Bevard3, Elizabeth Coleman3, Ian J. Sarembock3,4, , and Martin Alexander Schwartz1,2,3,5

1 Department of Microbiology, University of Virginia, Charlottesville, VA 22908
2 Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908
3 Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908
4 Internal Medicine, University of Virginia, Charlottesville, VA 22908
5 Mellon Prostate Cancer Research Center, University of Virginia, Charlottesville, VA 22908

Correspondence to M.A. Schwartz: maschwartz{at}virginia.edu

Abstract: Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-{kappa}B activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-{kappa}B activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-{kappa}B in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin {alpha}2ß1 on collagen prevents flow-induced NF-{kappa}B activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-{kappa}B activation, suggesting a novel therapeutic strategy for treating atherosclerosis.

Abbreviations used in this paper: ApoE, apolipoprotein E; BAE, bovine aortic endothelial; Coll, collagen; FG, fibrinogen; FN, fibronectin; IHC, immunohistochemistry; IKK, I{kappa}B kinase; LN, laminin.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Flow-dependent cellular mechanotransduction in atherosclerosis.
D. E. Conway and M. A. Schwartz (2013)
J. Cell Sci. 126, 5101-5109
   Abstract »    Full Text »    PDF »
MicroRNAs in flow-dependent vascular remodelling.
P. Neth, M. Nazari-Jahantigh, A. Schober, and C. Weber (2013)
Cardiovasc Res 99, 294-303
   Abstract »    Full Text »    PDF »
Altered nitric oxide production mediates matrix-specific PAK2 and NF-{kappa}B activation by flow.
A. Yurdagul Jr., J. Chen, S. D. Funk, P. Albert, C. G. Kevil, and A. W. Orr (2013)
Mol. Biol. Cell 24, 398-408
   Abstract »    Full Text »    PDF »
Endothelial shear stress in the evolution of coronary atherosclerotic plaque and vascular remodelling: current understanding and remaining questions.
J. J. Wentzel, Y. S. Chatzizisis, F. J. H. Gijsen, G. D. Giannoglou, C. L. Feldman, and P. H. Stone (2012)
Cardiovasc Res 96, 234-243
   Abstract »    Full Text »    PDF »
Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation.
I. Rohwedder, E. Montanez, K. Beckmann, E. Bengtsson, P. Duner, J. Nilsson, O. Soehnlein, and R. Fassler (2012)
EMBO Mol Med. 4, 564-576
   Abstract »    Full Text »    PDF »
Mechanosensitive mechanisms in transcriptional regulation.
A. Mammoto, T. Mammoto, and D. E. Ingber (2012)
J. Cell Sci. 125, 3061-3073
   Abstract »    Full Text »    PDF »
Carotid Intima-Media Thickness Progression in HIV-Infected Adults Occurs Preferentially at the Carotid Bifurcation and Is Predicted by Inflammation.
P. Y. Hsue, R. Scherzer, P. W. Hunt, A. Schnell, A. F. Bolger, S. C. Kalapus, K. Maka, J. N. Martin, P. Ganz, and S. G. Deeks (2012)
JAHA 1, jah3-e000422
   Abstract »    Full Text »    PDF »
Rip2 Deficiency Leads to Increased Atherosclerosis Despite Decreased Inflammation.
M. C. Levin, P. Jirholt, A. Wramstedt, M. E. Johansson, A. M. Lundberg, M. G. Trajkovska, M. Stahlman, P. Fogelstrand, M. Brisslert, L. Fogelstrand, et al. (2011)
Circ. Res. 109, 1210-1218
   Abstract »    Full Text »    PDF »
Immunization of apoE-/- mice with aldehyde-modified fibronectin inhibits the development of atherosclerosis.
P. Duner, F. To, K. Beckmann, H. Bjorkbacka, G. N. Fredrikson, J. Nilsson, and E. Bengtsson (2011)
Cardiovasc Res 91, 528-536
   Abstract »    Full Text »    PDF »
Hemodynamic Activation of {beta}-Catenin and T-Cell-Specific Transcription Factor Signaling in Vascular Endothelium Regulates Fibronectin Expression.
B. D. Gelfand, J. Meller, A. W. Pryor, M. Kahn, P. D. S. Bortz, B. R. Wamhoff, and B. R. Blackman (2011)
Arterioscler Thromb Vasc Biol 31, 1625-1633
   Abstract »    Full Text »    PDF »
Effects of Disturbed Flow on Vascular Endothelium: Pathophysiological Basis and Clinical Perspectives.
J.-J. Chiu and S. Chien (2011)
Physiol Rev 91, 327-387
   Abstract »    Full Text »    PDF »
p38 maintains E-cadherin expression by modulating TAK1-NF-{kappa}B during epithelial-to-mesenchymal transition.
R. Strippoli, I. Benedicto, M. Foronda, M. L. Perez-Lozano, S. Sanchez-Perales, M. Lopez-Cabrera, and M. A. del Pozo (2010)
J. Cell Sci. 123, 4321-4331
   Abstract »    Full Text »    PDF »
Shear stress: devil's in the details.
A. Hamik and M. K. Jain (2010)
Blood 116, 2625-2626
   Full Text »    PDF »
Direct-contact co-culture between smooth muscle and endothelial cells inhibits TNF-{alpha}-mediated endothelial cell activation.
C. S. Wallace and G. A. Truskey (2010)
Am J Physiol Heart Circ Physiol 299, H338-H346
   Abstract »    Full Text »    PDF »
{alpha}2{beta}1 integrin controls association of Rac with the membrane and triggers quiescence of endothelial cells.
L. Cailleteau, S. Estrach, R. Thyss, L. Boyer, A. Doye, B. Domange, N. Johnsson, E. Rubinstein, C. Boucheix, T. Ebrahimian, et al. (2010)
J. Cell Sci. 123, 2491-2501
   Abstract »    Full Text »    PDF »
Atheroprone Hemodynamics Regulate Fibronectin Deposition to Create Positive Feedback That Sustains Endothelial Inflammation.
R. E. Feaver, B. D. Gelfand, C. Wang, M. A. Schwartz, and B. R. Blackman (2010)
Circ. Res. 106, 1703-1711
   Abstract »    Full Text »    PDF »
Collagen I matrix turnover is regulated by fibronectin polymerization.
F. Shi, J. Harman, K. Fujiwara, and J. Sottile (2010)
Am J Physiol Cell Physiol 298, C1265-C1275
   Abstract »    Full Text »    PDF »
Matrix-Specific Protein Kinase A Signaling Regulates p21-Activated Kinase Activation by Flow in Endothelial Cells.
S. D. Funk, A. Yurdagul Jr, J. M. Green, K. A. Jhaveri, M. A. Schwartz, and A. W. Orr (2010)
Circ. Res. 106, 1394-1403
   Abstract »    Full Text »    PDF »
Endothelial cell responses to atheroprone flow are driven by two separate flow components: low time-average shear stress and fluid flow reversal.
D. E. Conway, M. R. Williams, S. G. Eskin, and L. V. McIntire (2010)
Am J Physiol Heart Circ Physiol 298, H367-H374
   Abstract »    Full Text »    PDF »
Fibulin-2 and Fibulin-5 Cooperatively Function to Form the Internal Elastic Lamina and Protect From Vascular Injury.
S. L. Chapman, F.- X. Sicot, E. C. Davis, J. Huang, T. Sasaki, M.-L. Chu, and H. Yanagisawa (2010)
Arterioscler Thromb Vasc Biol 30, 68-74
   Abstract »    Full Text »    PDF »
Focal adhesion kinase modulates activation of NF-{kappa}B by flow in endothelial cells.
T. Petzold, A. W. Orr, C. Hahn, K. A. Jhaveri, J. T. Parsons, and M. A. Schwartz (2009)
Am J Physiol Cell Physiol 297, C814-C822
   Abstract »    Full Text »    PDF »
Fibronectin Is an Important Regulator of Flow-Induced Vascular Remodeling.
H.-Y. Chiang, V. A. Korshunov, A. Serour, F. Shi, and J. Sottile (2009)
Arterioscler Thromb Vasc Biol 29, 1074-1079
   Abstract »    Full Text »    PDF »
The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow.
C. Hahn, A. W. Orr, J. M. Sanders, K. A. Jhaveri, and M. A. Schwartz (2009)
Circ. Res. 104, 995-1003
   Abstract »    Full Text »    PDF »
eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues.
J.-L. Balligand, O. Feron, and C. Dessy (2009)
Physiol Rev 89, 481-534
   Abstract »    Full Text »    PDF »
The Role of Cellular Adaptation to Mechanical Forces in Atherosclerosis.
C. Hahn and M. A. Schwartz (2008)
Arterioscler Thromb Vasc Biol 28, 2101-2107
   Abstract »    Full Text »    PDF »
Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation.
Y. Liu, D. T. Sweet, M. Irani-Tehrani, N. Maeda, and E. Tzima (2008)
J. Cell Biol. 182, 185-196
   Abstract »    Full Text »    PDF »
Integrin Agonists as Adjuvants in Chemotherapy for Melanoma.
M. A. Schwartz, K. McRoberts, M. Coyner, K. L. Andarawewa, H. F. Frierson Jr., J. M. Sanders, S. Swenson, F. Markland, M. R. Conaway, and D. Theodorescu (2008)
Clin. Cancer Res. 14, 6193-6197
   Abstract »    Full Text »    PDF »
What Underlies Endothelial Shear Sensing? The Matrix, of Course.
L. S. Terada (2008)
Circ. Res. 103, 562-564
   Full Text »    PDF »
p21-Activated Kinase Signaling Regulates Oxidant-Dependent NF-{kappa}B Activation by Flow.
A. W. Orr, C. Hahn, B. R. Blackman, and M. A. Schwartz (2008)
Circ. Res. 103, 671-679
   Abstract »    Full Text »    PDF »
GRP78 Upregulation by Atheroprone Shear Stress Via p38-, {alpha}2{beta}1-Dependent Mechanism in Endothelial Cells.
R. E. Feaver, N. E. Hastings, A. Pryor, and B. R. Blackman (2008)
Arterioscler Thromb Vasc Biol 28, 1534-1541
   Abstract »    Full Text »    PDF »
KLF2-dependent, Shear Stress-induced Expression of CD59: A NOVEL CYTOPROTECTIVE MECHANISM AGAINST COMPLEMENT-MEDIATED INJURY IN THE VASCULATURE.
A. R. Kinderlerer, F. Ali, M. Johns, E. A. Lidington, V. Leung, J. J. Boyle, S. S. Hamdulay, P. C. Evans, D. O. Haskard, and J. C. Mason (2008)
J. Biol. Chem. 283, 14636-14644
   Abstract »    Full Text »    PDF »
Atheroprotective Signaling Mechanisms Activated by Steady Laminar Flow in Endothelial Cells.
B. C. Berk (2008)
Circulation 117, 1082-1089
   Full Text »    PDF »
Fibronectin-dependent collagen I deposition modulates the cell response to fibronectin.
J. Sottile, F. Shi, I. Rublyevska, H.-Y. Chiang, J. Lust, and J. Chandler (2007)
Am J Physiol Cell Physiol 293, C1934-C1946
   Abstract »    Full Text »    PDF »
G Protein-Coupled Receptor Ca2+-Linked Mitochondrial Reactive Oxygen Species Are Essential for Endothelial/Leukocyte Adherence.
B. J. Hawkins, L. A. Solt, I. Chowdhury, A. S. Kazi, M. R. Abid, W. C. Aird, M. J. May, J. K. Foskett, and M. Madesh (2007)
Mol. Cell. Biol. 27, 7582-7593
   Abstract »    Full Text »    PDF »
Mapping the dynamics of shear stress-induced structural changes in endothelial cells.
R. E. Mott and B. P. Helmke (2007)
Am J Physiol Cell Physiol 293, C1616-C1626
   Abstract »    Full Text »    PDF »
Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis: Update and Therapeutic Implications.
I. Tabas, K. J. Williams, and J. Boren (2007)
Circulation 116, 1832-1844
   Abstract »    Full Text »    PDF »
Smooth muscle cell rigidity and extracellular matrix organization influence endothelial cell spreading and adhesion formation in coculture.
C. S. Wallace, S. A. Strike, and G. A. Truskey (2007)
Am J Physiol Heart Circ Physiol 293, H1978-H1986
   Abstract »    Full Text »    PDF »
Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis.
A. W. Orr, R. Stockton, M. B. Simmers, J. M. Sanders, I. J. Sarembock, B. R. Blackman, and M. A. Schwartz (2007)
J. Cell Biol. 176, 719-727
   Abstract »    Full Text »    PDF »
Matrix-specific Suppression of Integrin Activation in Shear Stress Signaling.
A. W. Orr, M. H. Ginsberg, S. J. Shattil, H. Deckmyn, and M. A. Schwartz (2006)
Mol. Biol. Cell 17, 4686-4697
   Abstract »    Full Text »    PDF »
Cell-Matrix Contact Prevents Recognition and Damage of Endothelial Cells in States of Heightened Immunity.
H. Methe and E. R. Edelman (2006)
Circulation 114, I-233-I-238
   Abstract »    Full Text »    PDF »
Laminin-10 and Lutheran blood group glycoproteins in adhesion of human endothelial cells.
N. Vainionpaa, Y. Kikkawa, K. Lounatmaa, J. H. Miner, P. Rousselle, and I. Virtanen (2006)
Am J Physiol Cell Physiol 290, C764-C775
   Abstract »    Full Text »    PDF »
Role of Small GTPases in Endothelial Cytoskeletal Dynamics and the Shear Stress Response.
E. Tzima (2006)
Circ. Res. 98, 176-185
   Abstract »    Full Text »    PDF »
Lipoprotein Retention--and Clues for Atheroma Regression.
K. J. Williams and I. Tabas (2005)
Arterioscler Thromb Vasc Biol 25, 1536-1540
   Abstract »    Full Text »    PDF »
The subendothelial extracellular matrix modulates NF-{kappa}B activation by flow: a potential role in atherosclerosis.
A. W. Orr, J. M. Sanders, M. Bevard, E. Coleman, I. J. Sarembock, and M. A. Schwartz (2005)
J. Exp. Med. 201, i12-12
   Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882