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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:2015.)
© 2003 American Heart Association, Inc.

Vascular Biology

Stent Implantation Activates Akt in the Vessel Wall

Role of Mechanical Stretch in Vascular Smooth Muscle Cells

Rui-Hai Zhou; Tzong-Shyuan Lee; Tsui-Chun Tsou; François Rannou; Yi-Shuan Li; Shu Chien; John Y.-J. Shyy

From the Division of Biomedical Sciences (R.-H.Z., T.-S.L., F.R., J.Y.-J.S.), University of California, Riverside, Calif; Department of Bioengineering and Whitaker Institute of Biomedical Engineering (T.-C.T., Y.-S.L., S.C.), University of California, San Diego, La Jolla, Calif; and Department of Geriatrics (R.-H.Z.), Shandong University Qilu Hospital, Jinan, Shandong, People’s Republic of China.

Correspondence to John Y.-J. Shyy, PhD, Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121. E-mail john.shyy{at}ucr.edu

Objective— The long-term efficacy of stent implantation is affected by in-stent restenosis (ISR). Multiple factors can contribute to ISR, and the underlying mechanism remains elusive. We investigated the possible role of mechanical stretch and the associated molecular signaling in ISR.

Methods and Results— Stent implantation in rat abdominal aortas induced neointima formation. Immunohistochemical studies revealed the activation of Akt in the media and neointima of the stented vessels. Western blotting showed increased phosphorylation of Akt at both Thr308 and Ser473 and phosphorylation of GSK-3ß in the stented vessels. A stretch device applying static equibiaxial stretch on cultured vascular smooth muscle cells was used to delineate the molecular mechanism underlying the stretch activation of Akt. Static mechanical stretch induced the sustained activation of Akt and its upstream phosphoinositide 3-kinase (PI3K) and the phosphorylation of GSK-3ß, its downstream effector in vascular smooth muscle cells. LY294002, a PI3K inhibitor, and N-acetylcysteine, a scavenger of reactive oxygen species, inhibited the stretch activation of Akt. Furthermore, N-acetylcysteine and wortmannin, another PI3K inhibitor, reduced the neointima formation after stent implantation.

Conclusions— Mechanical stretch of the vascular wall during stent deployment may contribute to ISR by activating the Akt pathway.

Key Words: vascular smooth muscle cells • stent • Akt • mechanical stretch • in-stent restenosis

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