Distinct Roles for the Small GTPases Cdc42 and Rho in Endothelial Responses to Shear Stress

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1999 Apr 20

PMID 10207166

Citations 58

Authors

S Li

B P Chen

N Azuma

Y L Hu

S Z Wu

B E Sumpio

J Y Shyy

S Chien

Affiliations

Soon will be listed here.

Abstract

Shear stress, the tangential component of hemodynamic forces, plays an important role in endothelial remodeling. In this study, we investigated the role of Rho family GTPases Cdc42 and Rho in shear stress-induced signal transduction and cytoskeleton reorganization. Our results showed that shear stress induced the translocation of Cdc42 and Rho from cytosol to membrane. Although both Cdc42 and Rho were involved in the shear stress-induced transcription factor AP-1 acting on the 12-O-tetradecanoyl-13-phorbol-acetate-responsive element (TRE), only Cdc42 was sufficient to activate AP-1/TRE. Dominant-negative mutants of Cdc42 and Rho, as well as recombinant C3 exoenzyme, attenuated the shear stress activation of c-Jun NH2-terminal kinases (JNKs), suggesting that Cdc42 and Rho regulate the shear stress induction of AP-1/TRE activity through JNKs. Shear stress-induced cell alignment and stress fiber formation were inhibited by the dominant-negative mutants of Rho and p160ROCK, but not by the dominant-negative mutant of Cdc42, indicating that the Rho-p160ROCK pathway regulates the cytoskeletal reorganization in response to shear stress.

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References

Ishizaki T, Naito M, Fujisawa K, Maekawa M, Watanabe N, Saito Y . p160ROCK, a Rho-associated coiled-coil forming protein kinase, works downstream of Rho and induces focal adhesions. FEBS Lett. 1997; 404(2-3):118-24. DOI: 10.1016/s0014-5793(97)00107-5. View

Ren X, Kiosses W, Schwartz M . Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J. 1999; 18(3):578-85. PMC: 1171150. DOI: 10.1093/emboj/18.3.578. View

Mizukami Y, Yoshioka K, Morimoto S, Yoshida K . A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion. J Biol Chem. 1997; 272(26):16657-62. DOI: 10.1074/jbc.272.26.16657. View

Van Aelst L, DSouza-Schorey C . Rho GTPases and signaling networks. Genes Dev. 1997; 11(18):2295-322. DOI: 10.1101/gad.11.18.2295. View

Aepfelbacher M, Essler M, Huber E, Sugai M, Weber P . Bacterial toxins block endothelial wound repair. Evidence that Rho GTPases control cytoskeletal rearrangements in migrating endothelial cells. Arterioscler Thromb Vasc Biol. 1997; 17(9):1623-9. DOI: 10.1161/01.atv.17.9.1623. View

Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T . Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997; 389(6654):990-4. DOI: 10.1038/40187. View

Li S, Kim M, Hu Y, Jalali S, Schlaepfer D, Hunter T . Fluid shear stress activation of focal adhesion kinase. Linking to mitogen-activated protein kinases. J Biol Chem. 1997; 272(48):30455-62. DOI: 10.1074/jbc.272.48.30455. View

Chien S, Li S, Shyy Y . Effects of mechanical forces on signal transduction and gene expression in endothelial cells. Hypertension. 1998; 31(1 Pt 2):162-9. DOI: 10.1161/01.hyp.31.1.162. View

Caro C, Fitz-Gerald J, Schroter R . 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. 1971; 177(1046):109-59. DOI: 10.1098/rspb.1971.0019. View

10.

Schwartz S, Haudenschild C, Eddy E . Endothelial regneration. I. Quantitative analysis of initial stages of endothelial regeneration in rat aortic intima. Lab Invest. 1978; 38(5):568-80. View

11.

Frangos J, Eskin S, McIntire L, Ives C . Flow effects on prostacyclin production by cultured human endothelial cells. Science. 1985; 227(4693):1477-9. DOI: 10.1126/science.3883488. View

12.

Ku D, Giddens D, Zarins C, Glagov S . Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis. 1985; 5(3):293-302. DOI: 10.1161/01.atv.5.3.293. View

13.

Levesque M, Nerem R . The elongation and orientation of cultured endothelial cells in response to shear stress. J Biomech Eng. 1985; 107(4):341-7. DOI: 10.1115/1.3138567. View

14.

Glagov S, Zarins C, Giddens D, Ku D . Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med. 1988; 112(10):1018-31. View

15.

Kim D, Gotlieb A, Langille B . In vivo modulation of endothelial F-actin microfilaments by experimental alterations in shear stress. Arteriosclerosis. 1989; 9(4):439-45. DOI: 10.1161/01.atv.9.4.439. View

16.

Ridley A, Hall A . The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992; 70(3):389-99. DOI: 10.1016/0092-8674(92)90163-7. View

17.

Ridley A, PATERSON H, Johnston C, Diekmann D, Hall A . The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992; 70(3):401-10. DOI: 10.1016/0092-8674(92)90164-8. View

18.

Hsieh H, Li N, Frangos J . Pulsatile and steady flow induces c-fos expression in human endothelial cells. J Cell Physiol. 1993; 154(1):143-51. DOI: 10.1002/jcp.1041540118. View

19.

RESNICK N, Collins T, Atkinson W, Bonthron D, Dewey Jr C, Gimbrone Jr M . Platelet-derived growth factor B chain promoter contains a cis-acting fluid shear-stress-responsive element. Proc Natl Acad Sci U S A. 1993; 90(10):4591-5. PMC: 46558. DOI: 10.1073/pnas.90.10.4591. View

20.

GIRARD P, Nerem R . Endothelial cell signaling and cytoskeletal changes in response to shear stress. Front Med Biol Eng. 1993; 5(1):31-6. View