Caveolin-1 facilitates mechanosensitive protein kinase B (Akt) signaling in vitro and in vivo.
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.
Sedding
Daniel G
DG
Department of Internal Medicine I/Cardiology, Giessen University, Giessen, Germany.
Hermsen
Jennifer
J
Seay
Ulrike
U
Eickelberg
Oliver
O
Kummer
Wolfgang
W
Schwencke
Carsten
C
Strasser
Ruth H
RH
Tillmanns
Harald
H
Braun-Dullaeus
Ruediger C
RC
D000714:Anastomosis, Surgical; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D017536:Carotid Artery, Common / Q000601:surgery; D021941:Caveolae / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D051242:Caveolin 1; D022461:Caveolins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured / Q000201:enzymology / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D022001:Focal Adhesions / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000502:physiology; D007601:Jugular Veins / Q000637:transplantation; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013314:Stress, Mechanical; D017539:Tunica Intima / Q000473:pathology; D000077191:Wortmannin; D047392:beta-Cyclodextrins / Q000494:pharmacology
D000730:Androstadienes; D051242:Caveolin 1; D022461:Caveolins; D002784:Cholesterol; D002867:Chromones; D048049:Extracellular Signal-Regulated MAP Kinases; D039302:Integrin alphaVbeta3; D008563:Membrane Lipids; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src); D011720:Pyrazoles; D011743:Pyrimidines; D000077191:Wortmannin; D047392:beta-Cyclodextrins; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C495541:Cav1 protein, mouse; C495537:Cav1 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494920:Akt1 protein, rat; C031215:betadex