Caveolin-1 Null Mice Are Viable but Show Evidence of Hyperproliferative and Vascular Abnormalities

Babak Razani, Jeffery A. Engelman, Xiao Bo Wang, William Schubert, Xiao Lan Zhang, Carolyn B. Marks, Frank Macalusol, Robert G. Russell, Maomi Li, Richard G. Pestell, Dolores Di Vizio, Harry Hou, Burkhard Kneitz, Guy Lagaud, George J. Christ, Winfried Edelmann, Michael P. Lisanti

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)38121-38138
Number of pages18
JournalJournal of Biological Chemistry
Volume276
Issue number41
StatePublished - Oct 12 2001

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Caveolin 1
Blood Vessels
Nitric Oxide Synthase Type III
Caveolae
Caveolins
Endothelial cells
Caveolin 2
Endocytosis
Endothelial Cells
Fibroblasts
Endothelium
Proteins
Cell Proliferation
Genetic Suppression
Ligands
Membranes
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor
Homologous Recombination
Cell proliferation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Razani, B., Engelman, J. A., Wang, X. B., Schubert, W., Zhang, X. L., Marks, C. B., ... Lisanti, M. P. (2001). Caveolin-1 Null Mice Are Viable but Show Evidence of Hyperproliferative and Vascular Abnormalities. Journal of Biological Chemistry, 276(41), 38121-38138.

Caveolin-1 Null Mice Are Viable but Show Evidence of Hyperproliferative and Vascular Abnormalities. / Razani, Babak; Engelman, Jeffery A.; Wang, Xiao Bo; Schubert, William; Zhang, Xiao Lan; Marks, Carolyn B.; Macalusol, Frank; Russell, Robert G.; Li, Maomi; Pestell, Richard G.; Di Vizio, Dolores; Hou, Harry; Kneitz, Burkhard; Lagaud, Guy; Christ, George J.; Edelmann, Winfried; Lisanti, Michael P.

In: Journal of Biological Chemistry, Vol. 276, No. 41, 12.10.2001, p. 38121-38138.

Research output: Contribution to journalArticle

Razani, B, Engelman, JA, Wang, XB, Schubert, W, Zhang, XL, Marks, CB, Macalusol, F, Russell, RG, Li, M, Pestell, RG, Di Vizio, D, Hou, H, Kneitz, B, Lagaud, G, Christ, GJ, Edelmann, W & Lisanti, MP 2001, 'Caveolin-1 Null Mice Are Viable but Show Evidence of Hyperproliferative and Vascular Abnormalities', Journal of Biological Chemistry, vol. 276, no. 41, pp. 38121-38138.
Razani B, Engelman JA, Wang XB, Schubert W, Zhang XL, Marks CB et al. Caveolin-1 Null Mice Are Viable but Show Evidence of Hyperproliferative and Vascular Abnormalities. Journal of Biological Chemistry. 2001 Oct 12;276(41):38121-38138.
Razani, Babak ; Engelman, Jeffery A. ; Wang, Xiao Bo ; Schubert, William ; Zhang, Xiao Lan ; Marks, Carolyn B. ; Macalusol, Frank ; Russell, Robert G. ; Li, Maomi ; Pestell, Richard G. ; Di Vizio, Dolores ; Hou, Harry ; Kneitz, Burkhard ; Lagaud, Guy ; Christ, George J. ; Edelmann, Winfried ; Lisanti, Michael P. / Caveolin-1 Null Mice Are Viable but Show Evidence of Hyperproliferative and Vascular Abnormalities. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 41. pp. 38121-38138.
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AU - Schubert, William

AU - Zhang, Xiao Lan

AU - Marks, Carolyn B.

AU - Macalusol, Frank

AU - Russell, Robert G.

AU - Li, Maomi

AU - Pestell, Richard G.

AU - Di Vizio, Dolores

AU - Hou, Harry

AU - Kneitz, Burkhard

AU - Lagaud, Guy

AU - Christ, George J.

AU - Edelmann, Winfried

AU - Lisanti, Michael P.

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