Caveolin-1 deficiency stimulates neointima formation during vascular injury.
Neointima formation is a process characterized by smooth muscle cell (SMC) proliferation and extracellular matrix deposition in the vascular intimal layer. Here, we critically evaluate the role of caveolin-1 (Cav-1) in the pathogenesis of neointima formation. Cav-1 and caveolae organelles are particularly abundant in SMCs, where they are thought to function in membrane trafficking and signal transduction events. To directly evaluate the role of Cav-1 in the pathogenesis of neointimal lesions, we used Cav-1-deficient (Cav-1 -/-) mice as a model system. The right common carotid artery of wild-type and Cav-1 -/- mice was ligated just proximal to its bifurcation. Specimens were then harvested 4-weeks postligation and processed for morphometric and immunohistochemical analyses. The carotids of Cav-1 -/- mice showed significantly more intimal hyperplasia with subtotal luminal obstruction, as compared to wild-type mice. These neointimal lesions consisted mainly of SMCs. Mechanistically, neointimal lesions derived from Cav-1 -/- mice exhibited higher levels of phospho-p42/44 MAP kinase and cyclin D1 immunostaining, consistent with the idea that Cav-1 functions as a negative regulator of signal transduction. A significant increase in phospho-Rb (Ser780) immunostaining was also observed, in line with the upregulation of cyclin D1. In conclusion, using a carotid artery blood-flow cessation model, we show that genetic ablation of Cav-1 in mice stimulates SMC proliferation (neointimal hyperplasia), with concomitant activation of the p42/44 MAP kinase cascade and upregulation of cyclin D1. Importantly, our current study is the first to investigate the role of Cav-1 in SMC proliferation in the vascular system using Cav-1 -/- mice.
Hassan
Ghada S
GS
Department of Molecular Pharmacology and The Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Jasmin
Jean-François
JF
Schubert
William
W
Frank
Philippe G
PG
Lisanti
Michael P
MP
D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics* / Q000502:physiology*; D002455:Cell Division; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000378:metabolism; D005838:Genotype; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008853:Microscopy; D008854:Microscopy, Electron; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases