Mechanosensitive p27Kip1 regulation and cell cycle entry in vascular smooth muscle cells

• Published in: Circulation (New York, N.Y.) Vol. 108; no. 5; pp. 616 - 622
• Main Authors: Sedding, Daniel G, Seay, Ulrike, Fink, Ludger, Heil, Matthias, Kummer, Wolfgang, Tillmanns, Harald, Braun-Dullaeus, Ruediger C
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 05-08-2003
• Subjects: Animals; Cell Cycle - physiology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p27; Down-Regulation - physiology; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Oligopeptides - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; RNA, Messenger - metabolism; Signal Transduction - physiology; Solubility; Stress, Mechanical; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000079102.08464.E2

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.
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 p27Kip1. This contrasted with the posttranscriptional protein reduction of p27Kip1 in cells stimulated with serum mitogens. Stretch-mediated p27Kip1 downregulation was accompanied by activation of cyclin-dependent kinase 2, hyperphosphorylation of retinoblastoma protein, and proliferation. Forkhead transcription factor inactivation and p27Kip1 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. p27Kip1 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.
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 p27Kip1, depending on the stimulus to which they are exposed. This observation has novel implications for understanding of vascular proliferative diseases.