Published online before print February 24, 2005, doi: 10.1161/01.RES.0000160610.61306.0f
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Submitted on September 18, 2003
Revised on February 15, 2005
Accepted on February 16, 2005
Caveolin-1 Facilitates Mechanosensitive Protein Kinase B (Akt) Signaling In Vitro and In Vivo
Daniel G. Sedding ;
From the Department of Internal Medicine I/Cardiology (D.G.S., J.H., H.T), Lung Center (U.S., O.E.), and Institute for Anatomy and Cell Biology (W.K.), Giessen University, Giessen, Germany; and the Department of Internal Medicine II/Cardiology (C.S., R.H.S., R.C.B.-D.), Dresden University of Technology, Dresden, Germany.
* To whom correspondence should be addressed. E-mail: r.braun-dullaeus{at}mailbox.tu-dresden.de.
Mechanotransduction represents an integral part of vascular homeostasis and contributes to vascular lesion formation. Previously, we demonstrated a mechanosensitive activation of phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt) resulting in p27Kip1 transcriptional downregulation and cell cycle entry of vascular smooth muscle cells (VSMC). In this study, we further elucidated the signaling from outside-in toward PI3-K/Akt in vitro and in an in vivo model of elevated tensile force. When VSMC were subjected to cyclic stretch (0.5 Hz at 125% resting length), PI3-K, Akt, and Src kinases were found activated. Disrupting caveolar structures with 
-cyclodextrin or transfection of VSMC with caveolin-1 antisense oligonucleotides (ODN) prevented PI3-K and Akt activation and cell cycle entry. Furthermore, PI3-K and Akt were resistant to activation when Src kinases were inhibited pharmacologically or by overexpression of a kinase-dead c-Src mutant. 
V3 integrins were identified to colocalize with PI3-K/caveolin-1 complexes, and blockade of V3 integrins prevented Akt activation. The central role of caveolin-1 in mechanotransduction was further examined in an in vivo model of elevated tensile force. Interposition of wild-type (WT) jugular veins into WT carotid arteries resulted in a rapid Akt activation within the veins that was almost abolished when veins of caveolin-1 knockout (KO) mice were used. Furthermore, late neointima formation within the KO veins was significantly reduced. Our study provides evidence that PI3-K/Akt is critically involved in mechanotransduction of VSMC in vitro and within the vasculature in vivo. Furthermore, caveolin-1 is essential for the integrin-mediated activation of PI3-K/Akt.
Key words: remodeling • muscle, smooth • signal transduction • stress • vasculature
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