Caveolin-2 is a member of the caveolin gene family with no known function. Although caveolin-2 is coexpressed and heterooligomerizes with caveolin-1 in many cell types (most notably adipocytes and endothelial cells), caveolin-2 has traditionally been considered the dispensable structural partner of the widely studied caveolin-1. We now directly address the functional significance of caveolin-2 by genetically targeting the caveolin-2 locus (Cav-2) in mice. In the absence of caveolin-2 protein expression, caveolae still form and caveolin-1 maintains its localization in plasma membrane caveolae, although in certain tissues caveolin-1 is partially destabilized and shows modestly diminished protein levels. Despite an intact caveolar membrane system, the Cav-2-null lung parenchyma shows hypercellularity, with thickened alveolar septa and an increase in the number of endothelial cells. As a result of these pathological changes, these Cav-2-null mice are markedly exercise intolerant. Interestingly, these Cav-2-null phenotypes are identical to the ones we and others have recently reported for Cav-1-null mice. As caveolin-2 expression is also severely reduced in Cav-1-null mice, we conclude that caveolin-2 deficiency is the clear culprit in this lung disorder. Our analysis of several different phenotypes observed in caveolin-1-deficient mice (i.e., abnormal vascular responses and altered lipid homeostasis) reveals that Cav-2-null mice do not show any of these other phenotypes, indicating a selective role for caveolin-2 in lung function. Taken together, our data show for the first time a specific role for caveolin-2 in mammalian physiology independent of caveolin-1. Caveolae were first morphologically described in the 1950s by early electron microscopists (31, 52). These curious 50-to 100-nm membrane invaginations are most commonly found in terminally differentiated cells, such as adipocytes, endothelial cells, smooth and skeletal muscle cells, and epithelial cells. In the ensuing years, several functions were proposed for these structures, including transcytosis, potocytosis, and the concentration of certain membrane proteins.A major advance in the study of caveolae was the discovery of the 21-to 24-kDa caveolar marker protein named caveolin (now called caveolin-1) (38). Along with concomitantly developed biochemical purification techniques, caveolin-1 served as an important means to identify such compartments and to study their function. The functional role of caveolin-1 is now a primary focus of the caveolar research field.In an effort to discover other novel resident proteins of caveolae, Scherer and colleagues identified a second caveolin homologue through the microsequencing of purified adipocyte caveolar membranes. This Ϸ20-kDa protein, named caveolin-2, was Ϸ38% identical and 58% similar to caveolin-1 (44). Further study showed that in many respects caveolin-2 was tightly coregulated with caveolin-1. The two tissues with the highest caveolin-1 expression (adipose tissue and lung) are also the primary sites of caveo...

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An arteriograph was used to assess myogenic tone, smooth muscle contractility and the influence of endothelial function on mesenteric resistance artery reactivity in insulin-resistant mice (C57BL/KsJ-db/db) and age- and gender-matched wild-type mice. Increases in transmural pressure induced myogenic tone in arteries from both control and db/db mice. At 12 and 16 weeks of age, greater tone developed in diabetic than in control mice. In control, but not in db/db mice, pretreatment of arteries with L-NAME potentiated myogenic tone. Indomethacin and SQ29548 (PGH₂/TXA₂ receptor antagonist) had no efffect in control, but inhibited myogenic tone in db/db mice. Endothelium-dependent vasodilation induced by acetylcholine and bradykinin, was depressed in db/db mice and potentiated by SQ29548 and LY333531 (protein kinase C_β inhibitor). Messenger RNA expression levels for PKC_β were over-expressed 2.5-fold in db/db relative to those in control mice. However, expression levels of mRNA for eNOS, PKC_α, and PKC_ξ were similar in the db/db and control mice. Collectively, these results suggest that the greater myogenic tone in resistance arteries from diabetic mice may be attributable, to greater amounts of one or more vasoconstricting prostanoids. Our data indicate that in diabetic mice, basal and agonist-stimulated NO releases are depressed and NO-mediated vasorelaxation in these mice may be countered by an endogenous vasoconstrictive prostanoid. This prostanoid-induced vasoconstriction is mediated by a PKC_β-dependent mechanism. Therefore, heightened activation of PKC_β and release of a vasoconstrictor prostanoid could play a role in endothelial dysfunction associated with type II diabetes.

The loss of Cav-1 and, thus, of most smooth muscle cell caveolae results in significant bladder dysfunction and urogenital organ changes in aged male mice.