title: Cooperative effects of matrix stiffness and fluid shear stress on endothelial cell behavior.
abstract: Arterial hemodynamic shear stress and blood vessel stiffening both significantly influence the arterial endothelial cell (EC) phenotype and atherosclerosis progression, and both have been shown to signal through cell-matrix adhesions. However, the cooperative effects of fluid shear stress and matrix stiffness on ECs remain unknown. To investigate these cooperative effects, we cultured bovine aortic ECs on hydrogels matching the elasticity of the intima of compliant, young, or stiff, aging arteries. The cells were then exposed to laminar fluid shear stress of 12 dyn/cm(2). Cells grown on more compliant matrices displayed increased elongation and tighter EC-cell junctions. Notably, cells cultured on more compliant substrates also showed decreased RhoA activation under laminar shear stress. Additionally, endothelial nitric oxide synthase and extracellular signal-regulated kinase phosphorylation in response to fluid shear stress occurred more rapidly in ECs cultured on more compliant substrates, and nitric oxide production was enhanced. Together, our results demonstrate that a signaling cross talk between stiffness and fluid shear stress exists within the vascular microenvironment, and, importantly, matrices mimicking young and healthy blood vessels can promote and augment the atheroprotective signals induced by fluid shear stress. These data suggest that targeting intimal stiffening and/or the EC response to intima stiffening clinically may improve vascular health.
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: Julie C
authors: JC
authors: Kohn
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: Dennis W
authors: DW
authors: Zhou
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: François
authors: F
authors: Bordeleau
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: Allen L
authors: AL
authors: Zhou
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: Brooke N
authors: BN
authors: Mason
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: Michael J
authors: MJ
authors: Mitchell
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: Michael R
authors: MR
authors: King
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York. Electronic address: cak57@cornell.edu.
authors: Cynthia A
authors: CA
authors: Reinhart-King
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000378:metabolism; D002417:Cattle; D048430:Cell Shape; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005453:Fluorescence; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D012212:Rheology; D033081:Shear Strength; D015398:Signal Transduction; D013314:Stress, Mechanical; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D048049:Extracellular Signal-Regulated MAP Kinases; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D020742:rhoA GTP-Binding Protein; D000099152:Cadherin 5
references: J Cell Sci. 2005 Sep 15;118(Pt 18):4103-11
references: 16118242
references: Trends Cell Biol. 2011 Nov;21(11):638-46
references: 21784638
references: J Biol Chem. 1997 Jan 10;272(2):1395-401
references: 8995450
references: Circ Res. 2006 Feb 3;98(2):176-85
references: 16456110
references: Anal Chem. 1998 Jul 1;70(13):2446-53
references: 9666719
references: J Biol Chem. 1997 Nov 28;272(48):30455-62
references: 9374537
references: Vascul Pharmacol. 2002 Nov;39(4-5):187-99
references: 12747959
references: J Biomech Eng. 1985 Nov;107(4):341-7
references: 4079361
references: Exp Dermatol. 2004 Feb;13(2):70-7
references: 15009099
references: Arterioscler Thromb Vasc Biol. 1998 May;18(5):677-85
references: 9598824
references: J Cell Sci. 1996 Apr;109 ( Pt 4):713-26
references: 8718663
references: Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2332-9
references: 17761936
references: Mol Cell Biol. 2002 Dec;22(24):8467-77
references: 12446767
references: J Cell Biol. 2003 Apr 28;161(2):429-39
references: 12719476
references: Nature. 2005 Sep 15;437(7057):426-31
references: 16163360
references: Cell Physiol Biochem. 2013;32(4):899-914
references: 24217646
references: Biophys J. 2004 Apr;86(4):2558-65
references: 15041692
references: J Biol Chem. 2005 Mar 25;280(12):11185-91
references: 15668248
references: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13661-5
references: 9391082
references: Biochem Biophys Res Commun. 2013 Nov 29;441(4):713-9
references: 24211212
references: Chem Pharm Bull (Tokyo). 1998 Feb;46(2):373-5
references: 9501473
references: Biotechnol Bioeng. 2014 Jan;111(1):184-95
references: 23842728
references: Dev Cell. 2009 Feb;16(2):209-21
references: 19217423
references: Cancer Cell. 2006 Jan;9(1):33-44
references: 16413470
references: Life Sci. 2006 Jun 13;79(3):233-9
references: 16458937
references: Ann Biomed Eng. 2008 Apr;36(4):554-62
references: 18172767
references: Biomech Model Mechanobiol. 2012 Mar;11(3-4):461-73
references: 21744269
references: J Cell Physiol. 2005 Jul;204(1):198-209
references: 15669099
references: Curr Opin Lipidol. 2012 Oct;23(5):446-52
references: 22964993
references: Cancer Cell. 2005 Sep;8(3):241-54
references: 16169468
references: Cell Mol Bioeng. 2013 Jun;6(2):null
references: 24348877
references: Atherosclerosis. 2014 Nov;237(1):208-19
references: 25244505
references: Sci Transl Med. 2011 Dec 7;3(112):112ra122
references: 22158860
references: Biophys J. 2009 Sep 2;97(5):1313-22
references: 19720019
references: Microvasc Res. 2013 May;87:50-7
references: 23296034
references: Free Radic Biol Med. 2012 Mar 15;52(6):1093-100
references: 22281399
references: J Biomech. 2011 Mar 15;44(5):815-21
references: 21288524
references: EMBO J. 2001 Sep 3;20(17):4639-47
references: 11532928
references: J Biomech Eng. 1981 Aug;103(3):172-6
references: 7278195
references: Arterioscler Thromb Vasc Biol. 2005 Dec;25(12):2548-53
references: 16195476
references: J Biol Chem. 2002 Feb 1;277(5):3388-96
references: 11729190
references: Am J Physiol Cell Physiol. 2010 Sep;299(3):C621-9
references: 20554908