Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities.

By B. Razani, Jeffery A. Engelman, Xiaobo Wang, W. Schubert, Xiao Lan Zhang, Carolyn B. Marks, F. Macaluso, R. Russell, Maomi Li, R. Pestell and 7 more. Journal of Biological Chemistry, 2001

1,226 citations recorded by the source corpus.

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.

Subfields: Cell Biology

View Paper: https://www.semanticscholar.org/paper/751aa988df5ab3acb826d3c1f351e4fb07023ea2

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Citations in the corpus

• Caveolae: From Cell Biology to Animal Physiology (2002, methodology): “Despite the down-regulation of Cav-1 in numerous tumors and its ability to regulate several oncogenic pathways (both suggestive of a tumor-suppressive role), Cav-1 null mice do not present with a higher incidence of carcinomas (Razani et al., 2001a).”
• Caveolae/raft-dependent endocytosis (2003, background): “Key words: endocytosis; caveolae; glycolipid rafts; caveolin; dynamin Th e Jo ur na l o f C el l B io lo gy 674 The Journal of Cell Biology | Volume 161, Number 4, 2003 et al., 2000; Razani et al., 2001).”
• Role of caveolae and caveolins in health and disease. (2004, methodology): “However, Cav-2 null mice do display marked lung pathology, similar to that described in Cav-1 null mice (40, 198, 199).”
• Biomechanical remodeling of the microenvironment by stromal Caveolin-1 favors tumor invasion and metastasis (2011, methodology): “Disturbed fibroblast function might underlie pulmonary fibrosis, hypertension, and cardiac fibrosis and hypertrophy in Cav1KO mice (Drab, 2001; Razani et al., 2001; Zhao et al., 2002).”
• Stepwise Recruitment of Transcellular and Paracellular Pathways Underlies Blood-Brain Barrier Breakdown in Stroke (2014, neutral): “P A A uthor M anuscript vessels at 27 h, in either wild-type or Cav1-deficient mice that lack EC caveolae (Drab et al., 2001; Razani et al., 2001).”
• Lipid Rafts and Caveolae as Portals for Endocytosis: New Insights and Common Mechanisms (2003, background): “However, other studies showed that endocytosis and transcytosis of albumin was significantly impaired in the endothelium of caveolin-1 null mice (11,43).”
• Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. (2003, neutral): “In aortas from caveolin knockout mice, on the other hand, the relaxant response to acetylcholine is enhanced and the constrictor response to phenylephrine blunted as a consequence of enhanced basal NO production (29, 103).”
• Routes and mechanisms of extracellular vesicle uptake (2014, background): “CAV1 null mice show phenotypic changes in vasculature but are viable (106), suggesting that either CAV1 is not essential for full EV uptake or that the ability to internalize vesicles via CDE is not essential for viability.”