Published Online
on June 30, 2003

A more recent version of this article appeared on August 5, 2003

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Submitted on November 13, 2002
Revised on March 25, 2003
Accepted on March 27, 2003

Mechanosensitive p27^Kip1 Regulation and Cell Cycle Entry in Vascular Smooth Muscle Cells

Daniel G. Sedding MD, Ulrike Seay , Ludger Fink MD, Matthias Heil PhD, Wolfgang Kummer MD, Harald Tillmanns MD, and Ruediger C. Braun-Dullaeus MD^*

From the Departments of Internal Medicine/Cardiology (D.G.S., U.S., H.T., R.C.B.-D.) and Pathology (L.F.), and the Institute for Anatomy and Cell Biology (W.G.), Giessen University, Giessen, and the Max-Planck-Institute of Physiology and Clinical Research (M.H.), Bad Nauheim, Germany.

^* To whom correspondence should be addressed. E-mail: ruediger.braun-dullaeus{at}innere.med.uni-giessen.de.

Background--Cyclic stretch plays an important role in the homeostasis of vessel structure. Increased forces might, however, contribute to remodeling processes, resulting in vascular proliferative diseases. The initial molecular events necessary for mechanosensitive cell cycle entry of quiescent smooth muscle cells are poorly understood.

Methods and Results--In this study, we demonstrate that mechanical strain resulted in a rapid, integrin-dependent but mitogen-independent activation of phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt) in quiescent vascular smooth muscle cells. Subsequently, downstream ALL 1 fused gene from chromosome X (AFX)-like forkhead transcription factors were inactivated, leading to transcriptional downregulation of p27^Kip1. This contrasted with the posttranscriptional protein reduction of p27^Kip1 in cells stimulated with serum mitogens. Stretch-mediated p27^Kip1 downregulation was accompanied by activation of cyclin-dependent kinase 2, hyperphosphorylation of retinoblastoma protein, and proliferation. Forkhead transcription factor inactivation and p27^Kip1 downregulation were prevented by the PI3-K inhibitors wortmannin and LY294002. Pharmacological blockade of other kinases, such as p42/44, p38, and protein kinase A or C, did not influence the mechanosensitive gene regulation. p27^Kip1 downregulation and cell cycle entry were, however, prevented by overexpression of a constitutively inactive form of Akt or constitutively active forms of forkhead transcription factors.

Conclusions--Our data demonstrate that the earliest cell cycle events can occur in a solely mechanosensitive fashion. Vascular smooth muscle cells are, furthermore, able to use transcriptional or posttranscriptional mechanisms to regulate p27^Kip1, depending on the stimulus to which they are exposed. This observation has novel implications for understanding of vascular proliferative diseases.

Key words: remodeling • muscle, smooth • signal transduction • stress • vasculature

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