RGD Reference Report - Caveolin-1 facilitates mechanosensitive protein kinase B (Akt) signaling in vitro and in vivo. - Rat Genome Database

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Caveolin-1 facilitates mechanosensitive protein kinase B (Akt) signaling in vitro and in vivo.

Authors: Sedding, DG  Hermsen, J  Seay, U  Eickelberg, O  Kummer, W  Schwencke, C  Strasser, RH  Tillmanns, H  Braun-Dullaeus, RC 
Citation: Sedding DG, etal., Circ Res. 2005 Apr 1;96(6):635-42. Epub 2005 Feb 24.
RGD ID: 1582182
Pubmed: PMID:15731459   (View Abstract at PubMed)
DOI: DOI:10.1161/01.RES.0000160610.61306.0f   (Journal Full-text)

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 beta-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. alpha(V)beta3 integrins were identified to colocalize with PI3-K/caveolin-1 complexes, and blockade of alpha(V)beta3 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.

Gene Ontology Annotations    

Biological Process

Cellular Component

Objects Annotated

Genes (Rattus norvegicus)
Cav1  (caveolin 1)
Src  (SRC proto-oncogene, non-receptor tyrosine kinase)

Objects referenced in this article
Gene Fyn FYN proto-oncogene, Src family tyrosine kinase Rattus norvegicus
Gene Pik3r1 phosphoinositide-3-kinase regulatory subunit 1 Rattus norvegicus
Gene Yes1 YES proto-oncogene 1, Src family tyrosine kinase Rattus norvegicus

Additional Information