title: Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities.
abstract: Caveolin-1 is the principal structural protein of caveolae membranes in fibroblasts and endothelia. Recently, we have shown that the human CAV-1 gene is localized to a suspected tumor suppressor locus, and mutations in Cav-1 have been implicated in human cancer. Here, we created a caveolin-1 null (CAV-1 -/-) mouse model, using standard homologous recombination techniques, to assess the role of caveolin-1 in caveolae biogenesis, endocytosis, cell proliferation, and endothelial nitric-oxide synthase (eNOS) signaling. Surprisingly, Cav-1 null mice are viable. We show that these mice lack caveolin-1 protein expression and plasmalemmal caveolae. In addition, analysis of cultured fibroblasts from Cav-1 null embryos reveals the following: (i) a loss of caveolin-2 protein expression; (ii) defects in the endocytosis of a known caveolar ligand, i.e. fluorescein isothiocyanate-albumin; and (iii) a hyperproliferative phenotype. Importantly, these phenotypic changes are reversed by recombinant expression of the caveolin-1 cDNA. Furthermore, examination of the lung parenchyma (an endothelial-rich tissue) shows hypercellularity with thickened alveolar septa and an increase in the number of vascular endothelial growth factor receptor (Flk-1)-positive endothelial cells. As predicted, endothelial cells from Cav-1 null mice lack caveolae membranes. Finally, we examined eNOS signaling by measuring the physiological response of aortic rings to various stimuli. Our results indicate that eNOS activity is up-regulated in Cav-1 null animals, and this activity can be blunted by using a specific NOS inhibitor, nitro-l-arginine methyl ester. These findings are in accordance with previous in vitro studies showing that caveolin-1 is an endogenous inhibitor of eNOS. Thus, caveolin-1 expression is required to stabilize the caveolin-2 protein product, to mediate the caveolar endocytosis of specific ligands, to negatively regulate the proliferation of certain cell types, and to provide tonic inhibition of eNOS activity in endothelial cells.
authors.affiliation: Department of Molecular Pharmacology and The Albert Einstein Cancer Center, The Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: B
authors.initials: B
authors.lastname: Razani
authors.forename: J A
authors.initials: JA
authors.lastname: Engelman
authors.forename: X B
authors.initials: XB
authors.lastname: Wang
authors.forename: W
authors.initials: W
authors.lastname: Schubert
authors.forename: X L
authors.initials: XL
authors.lastname: Zhang
authors.forename: C B
authors.initials: CB
authors.lastname: Marks
authors.forename: F
authors.initials: F
authors.lastname: Macaluso
authors.forename: R G
authors.initials: RG
authors.lastname: Russell
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: R G
authors.initials: RG
authors.lastname: Pestell
authors.forename: D
authors.initials: D
authors.lastname: Di Vizio
authors.forename: H
authors.initials: H
authors.lastname: Hou
authors.forename: B
authors.initials: B
authors.lastname: Kneitz
authors.forename: G
authors.initials: G
authors.lastname: Lagaud
authors.forename: G J
authors.initials: GJ
authors.lastname: Christ
authors.forename: W
authors.initials: W
authors.lastname: Edelmann
authors.forename: M P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division / Q000235:genetics*; D017931:DNA Primers; D004705:Endocytosis; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism*; D018390:Gene Targeting; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010641:Phenotype; D015398:Signal Transduction; D014168:Transferrin / Q000378:metabolism
chemical_list: D000418:Albumins; C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D017931:DNA Primers; D014168:Transferrin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse