KEGG   PATHWAY: mmu05418
mmu05418                    Pathway                                
Fluid shear stress and atherosclerosis - Mus musculus (house mouse)
Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall and plays a central role in vascular biology and contributes to the progress of atherosclerosis. Sustained laminar flow with high shear stress upregulates expressions of endothelial cell (EC) genes and proteins that are protective against atherosclerosis. The key shear stress-induced transcription factors that govern the expression of these genes are Kruppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2). On the other hand, disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote oxidative and inflammatory states in the artery wall, resulting in atherogenesis. Important transcriptional events that reflect this condition of ECs in disturbed flow include the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB).
Human Diseases; Cardiovascular disease
Pathway map
mmu05418  Fluid shear stress and atherosclerosis

Mus musculus (house mouse) [GN:mmu]
15519  Hsp90aa1; heat shock protein 90, alpha (cytosolic), class A member 1 [KO:K04079]
15516  Hsp90ab1; heat shock protein 90 alpha (cytosolic), class B member 1 [KO:K04079]
22027  Hsp90b1; heat shock protein 90, beta (Grp94), member 1 [KO:K09487]
18127  Nos3; nitric oxide synthase 3, endothelial cell [KO:K13242] [EC:]
12389  Cav1; caveolin 1, caveolae protein [KO:K06278]
12390  Cav2; caveolin 2 [KO:K12958]
12391  Cav3; caveolin 3 [KO:K12959]
12313  Calm1; calmodulin 1 [KO:K02183]
80796  Calm4; calmodulin 4 [KO:K02183]
12315  Calm3; calmodulin 3 [KO:K02183]
12314  Calm2; calmodulin 2 [KO:K02183]
70405  Calml3; calmodulin-like 3 [KO:K02183]
494124  Calm5; calmodulin 5 [KO:K02183]
75600  Calml4; calmodulin-like 4 [KO:K02183]
14733  Gpc1; glypican 1 [KO:K08107]
20969  Sdc1; syndecan 1 [KO:K06257]
15529  Sdc2; syndecan 2 [KO:K16336]
20971  Sdc4; syndecan 4 [KO:K16338]
63873  Trpv4; transient receptor potential cation channel, subfamily V, member 4 [KO:K04973]
50868  Keap1; kelch-like ECH-associated protein 1 [KO:K10456]
18024  Nfe2l2; nuclear factor, erythroid derived 2, like 2 [KO:K05638]
15368  Hmox1; heme oxygenase 1 [KO:K00510] [EC:]
14858  Gsta2; glutathione S-transferase, alpha 2 (Yc2) [KO:K00799] [EC:]
14859  Gsta3; glutathione S-transferase, alpha 3 [KO:K00799] [EC:]
14860  Gsta4; glutathione S-transferase, alpha 4 [KO:K00799] [EC:]
14862  Gstm1; glutathione S-transferase, mu 1 [KO:K00799] [EC:]
14863  Gstm2; glutathione S-transferase, mu 2 [KO:K00799] [EC:]
14866  Gstm5; glutathione S-transferase, mu 5 [KO:K00799] [EC:]
14867  Gstm6; glutathione S-transferase, mu 6 [KO:K00799] [EC:]
14871  Gstt1; glutathione S-transferase, theta 1 [KO:K00799] [EC:]
14872  Gstt2; glutathione S-transferase, theta 2 [KO:K00799] [EC:]
14873  Gsto1; glutathione S-transferase omega 1 [KO:K00799] [EC:]
14864  Gstm3; glutathione S-transferase, mu 3 [KO:K00799] [EC:]
66447  Mgst3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:]
14857  Gsta1; glutathione S-transferase, alpha 1 (Ya) [KO:K00799] [EC:]
56615  Mgst1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:]
68214  Gsto2; glutathione S-transferase omega 2 [KO:K00799] [EC:]
68312  Gstm7; glutathione S-transferase, mu 7 [KO:K00799] [EC:]
14865  Gstm4; glutathione S-transferase, mu 4 [KO:K00799] [EC:]
211666  Mgst2; microsomal glutathione S-transferase 2 [KO:K00799] [EC:]
100042295  Gm3776; predicted gene 3776 [KO:K00799] [EC:]
100042314  Gsta5; glutathione S-transferase alpha 5 [KO:K00799] [EC:]
103140  Gstt3; glutathione S-transferase, theta 3 [KO:K00799] [EC:]
75886  Gstt4; glutathione S-transferase, theta 4 [KO:K00799] [EC:]
14870  Gstp1; glutathione S-transferase, pi 1 [KO:K23790] [EC:]
14869  Gstp2; glutathione S-transferase, pi 2 [KO:K23790] [EC:]
225884  Gstp3; glutathione S-transferase pi 3 [KO:K23790] [EC:]
18104  Nqo1; NAD(P)H dehydrogenase, quinone 1 [KO:K00355] [EC:]
18412  Sqstm1; sequestosome 1 [KO:K14381]
22166  Txn1; thioredoxin 1 [KO:K03671]
56551  Txn2; thioredoxin 2 [KO:K03671]
18159  Nppc; natriuretic peptide type C [KO:K12336]
11898  Ass1; argininosuccinate synthetase 1 [KO:K01940] [EC:]
21824  Thbd; thrombomodulin [KO:K03907]
18791  Plat; plasminogen activator, tissue [KO:K01343] [EC:]
12562  Cdh5; cadherin 5 [KO:K06533]
16542  Kdr; kinase insert domain protein receptor [KO:K05098] [EC:]
12387  Ctnnb1; catenin (cadherin associated protein), beta 1 [KO:K02105]
105787  Prkaa1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:]
108079  Prkaa2; protein kinase, AMP-activated, alpha 2 catalytic subunit [KO:K07198] [EC:]
18613  Pecam1; platelet/endothelial cell adhesion molecule 1 [KO:K06471]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:]
23938  Map2k5; mitogen-activated protein kinase kinase 5 [KO:K04463] [EC:]
23939  Mapk7; mitogen-activated protein kinase 7 [KO:K04464] [EC:]
17258  Mef2a; myocyte enhancer factor 2A [KO:K09260]
17260  Mef2c; myocyte enhancer factor 2C [KO:K04454]
16598  Klf2; Kruppel-like factor 2 (lung) [KO:K17845]
16399  Itga2b; integrin alpha 2b [KO:K06476]
16410  Itgav; integrin alpha V [KO:K06487]
16416  Itgb3; integrin beta 3 [KO:K06493]
20779  Src; Rous sarcoma oncogene [KO:K05704] [EC:]
14083  Ptk2; PTK2 protein tyrosine kinase 2 [KO:K05725] [EC:]
16800  Arhgef2; rho/rac guanine nucleotide exchange factor (GEF) 2 [KO:K12791]
11848  Rhoa; ras homolog family member A [KO:K04513]
67653  4930544G11Rik; RIKEN cDNA 4930544G11 gene [KO:K04513]
11465  Actg1; actin, gamma, cytoplasmic 1 [KO:K05692]
11461  Actb; actin, beta [KO:K05692]
19252  Dusp1; dual specificity phosphatase 1 [KO:K21278] [EC:]
723893  Mir10a; microRNA 10a [KO:K16864]
21937  Tnfrsf1a; tumor necrosis factor receptor superfamily, member 1a [KO:K03158]
16177  Il1r1; interleukin 1 receptor, type I [KO:K04386]
16178  Il1r2; interleukin 1 receptor, type II [KO:K04387]
26409  Map3k7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:]
16151  Ikbkg; inhibitor of kappaB kinase gamma [KO:K07210]
12675  Chuk; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:]
16150  Ikbkb; inhibitor of kappaB kinase beta [KO:K07209] [EC:]
18033  Nfkb1; nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105 [KO:K02580]
19697  Rela; v-rel reticuloendotheliosis viral oncogene homolog A (avian) [KO:K04735]
26408  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:]
26398  Map2k4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:]
26400  Map2k7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:]
26419  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
26420  Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
26414  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:]
26399  Map2k6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:]
26416  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
19094  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
29857  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
26415  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
14281  Fos; FBJ osteosarcoma oncogene [KO:K04379]
16476  Jun; jun proto-oncogene [KO:K04448]
17390  Mmp2; matrix metallopeptidase 2 [KO:K01398] [EC:]
17395  Mmp9; matrix metallopeptidase 9 [KO:K01403] [EC:]
13039  Ctsl; cathepsin L [KO:K01365] [EC:]
20296  Ccl2; chemokine (C-C motif) ligand 2 [KO:K14624]
20293  Ccl12; chemokine (C-C motif) ligand 12 [KO:K14624]
22329  Vcam1; vascular cell adhesion molecule 1 [KO:K06527]
15894  Icam1; intercellular adhesion molecule 1 [KO:K06490]
20339  Sele; selectin, endothelial cell [KO:K06494]
21926  Tnf; tumor necrosis factor [KO:K03156]
16175  Il1a; interleukin 1 alpha [KO:K04383]
16176  Il1b; interleukin 1 beta [KO:K04519]
15978  Ifng; interferon gamma [KO:K04687]
18590  Pdgfa; platelet derived growth factor, alpha [KO:K04359]
18591  Pdgfb; platelet derived growth factor, B polypeptide [KO:K17386]
13614  Edn1; endothelin 1 [KO:K16366]
22339  Vegfa; vascular endothelial growth factor A [KO:K05448]
12159  Bmp4; bone morphogenetic protein 4 [KO:K04662]
12168  Bmpr2; bone morphogenetic protein receptor, type II (serine/threonine kinase) [KO:K04671] [EC:]
11481  Acvr2b; activin receptor IIB [KO:K13596] [EC:]
11480  Acvr2a; activin receptor IIA [KO:K13596] [EC:]
11477  Acvr1; activin A receptor, type 1 [KO:K04675] [EC:]
12166  Bmpr1a; bone morphogenetic protein receptor, type 1A [KO:K04673] [EC:]
12167  Bmpr1b; bone morphogenetic protein receptor, type 1B [KO:K13578] [EC:]
237038  Nox1; NADPH oxidase 1 [KO:K08008]
13057  Cyba; cytochrome b-245, alpha polypeptide [KO:K08009]
17969  Ncf1; neutrophil cytosolic factor 1 [KO:K08011]
17970  Ncf2; neutrophil cytosolic factor 2 [KO:K08010]
19353  Rac1; Rac family small GTPase 1 [KO:K04392]
19354  Rac2; Rac family small GTPase 2 [KO:K07860]
170758  Rac3; Rac family small GTPase 3 [KO:K07861]
18762  Prkcz; protein kinase C, zeta [KO:K18952] [EC:]
59004  Pias4; protein inhibitor of activated STAT 4 [KO:K16065] [EC:]
22059  Trp53; transformation related protein 53 [KO:K04451]
170930  Sumo2; small ubiquitin-like modifier 2 [KO:K12160]
20610  Sumo3; small ubiquitin-like modifier 3 [KO:K12160]
22218  Sumo1; small ubiquitin-like modifier 1 [KO:K12160]
102640040  Gm11971; predicted gene 11971 [KO:K12160]
101056240  Gm13430; predicted gene 13430 [KO:K12160]
12043  Bcl2; B cell leukemia/lymphoma 2 [KO:K02161]
C00076  Calcium cation
C00272  Tetrahydrobiopterin
C00518  Hyaluronate
C00533  Nitric oxide
C00607  Chondroitin sulfate
C00704  Superoxide
C00925  Heparan sulfate
C16845  Peroxynitrite
Nigro P, Abe J, Berk BC
Flow shear stress and atherosclerosis: a matter of site specificity.
Antioxid Redox Signal 15:1405-14 (2011)
McSweeney SR, Warabi E, Siow RC
Nrf2 as an Endothelial Mechanosensitive Transcription Factor: Going With the Flow.
Hypertension 67:20-9 (2016)
Heo KS, Fujiwara K, Abe J
Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction.
Circ J 75:2722-30 (2011)
Wild J, Soehnlein O, Dietel B, Urschel K, Garlichs CD, Cicha I
Rubbing salt into wounded endothelium: sodium potentiates proatherogenic effects of TNF-alpha under non-uniform shear stress.
Thromb Haemost 112:183-95 (2014)
Noguchi N, Jo H
Redox going with vascular shear stress.
Antioxid Redox Signal 15:1367-8 (2011)
Li X, Yang Q, Wang Z, Wei D
Shear stress in atherosclerotic plaque determination.
DNA Cell Biol 33:830-8 (2014)
Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH
Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior.
J Am Coll Cardiol 49:2379-93 (2007)
Lu D, Kassab GS
Role of shear stress and stretch in vascular mechanobiology.
J R Soc Interface 8:1379-85 (2011)
Givens C, Tzima E
Endothelial Mechanosignaling: Does One Sensor Fit All?
Antioxid Redox Signal 25:373-88 (2016)
Paravicini TM, Touyz RM
Redox signaling in hypertension.
Cardiovasc Res 71:247-58 (2006)
Boon RA, Horrevoets AJ
Key transcriptional regulators of the vasoprotective effects of shear stress.
Hamostaseologie 29:39-40, 41-3 (2009)
Bryan MT, Duckles H, Feng S, Hsiao ST, Kim HR, Serbanovic-Canic J, Evans PC
Mechanoresponsive networks controlling vascular inflammation.
Arterioscler Thromb Vasc Biol 34:2199-205 (2014)
Brown AJ, Teng Z, Evans PC, Gillard JH, Samady H, Bennett MR
Role of biomechanical forces in the natural history of coronary atherosclerosis.
Nat Rev Cardiol 13:210-20 (2016)
Zhou J, Li YS, Chien S
Shear stress-initiated signaling and its regulation of endothelial function.
Arterioscler Thromb Vasc Biol 34:2191-8 (2014)
Liu HB, Zhang J, Xin SY, Liu C, Wang CY, Zhao D, Zhang ZR
Mechanosensitive properties in the endothelium and their roles in the regulation of endothelial function.
J Cardiovasc Pharmacol 61:461-70 (2013)
Boon RA, Leyen TA, Fontijn RD, Fledderus JO, Baggen JM, Volger OL, van Nieuw Amerongen GP, Horrevoets AJ
KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium.
Blood 115:2533-42 (2010)
Whyte JJ, Laughlin MH
The effects of acute and chronic exercise on the vasculature.
Acta Physiol (Oxf) 199:441-50 (2010)
Quillon A, Fromy B, Debret R
Endothelium microenvironment sensing leading to nitric oxide mediated vasodilation: a review of nervous and biomechanical signals.
Nitric Oxide 45:20-6 (2015)
Sorescu GP, Song H, Tressel SL, Hwang J, Dikalov S, Smith DA, Boyd NL, Platt MO, Lassegue B, Griendling KK, Jo H
Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase.
Circ Res 95:773-9 (2004)
Hopkins PN
Molecular biology of atherosclerosis.
Physiol Rev 93:1317-542 (2013)
Johnson BD, Mather KJ, Wallace JP
Mechanotransduction of shear in the endothelium: basic studies and clinical implications.
Vasc Med 16:365-77 (2011)
Hu LS, George J, Wang JH
Current concepts on the role of nitric oxide in portal hypertension.
World J Gastroenterol 19:1707-17 (2013)
Collins C, Guilluy C, Welch C, O'Brien ET, Hahn K, Superfine R, Burridge K, Tzima E
Localized tensional forces on PECAM-1 elicit a global mechanotransduction response via the integrin-RhoA pathway.
Curr Biol 22:2087-94 (2012)
Conway DE, Schwartz MA
Flow-dependent cellular mechanotransduction in atherosclerosis.
J Cell Sci 126:5101-9 (2013)
Chen J, Green J, Yurdagul A Jr, Albert P, McInnis MC, Orr AW
alphavbeta3 Integrins Mediate Flow-Induced NF-kappaB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation.
Am J Pathol 185:2575-89 (2015)
Nigro P, Abe J, Woo CH, Satoh K, McClain C, O'Dell MR, Lee H, Lim JH, Li JD, Heo KS, Fujiwara K, Berk BC
PKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5.
Blood 116:1971-9 (2010)
mmu04010  MAPK signaling pathway
mmu04064  NF-kappa B signaling pathway
mmu04151  PI3K-Akt signaling pathway
mmu04210  Apoptosis
mmu04270  Vascular smooth muscle contraction
mmu04510  Focal adhesion
mmu04514  Cell adhesion molecules
mmu04670  Leukocyte transendothelial migration
KO pathway

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