Out of the Caves

Abstract

Caveolae, "little caves" consisting of flask-shaped invaginations of the plasma membrane, form distinct membrane domains that have been implicated in nitric oxide (NO), insulin, and calcium signal transduction, presumably through localization of signaling proteins in caveolae and their specific interactions with caveolar proteins or lipids. Caveolins are integral membrane proteins that are found in caveolae and are required for caveolar formation in endothelial cells and myocytes. Elimination of caveolins thus interferes with both the formation of caveolae and any specific interactions between caveolins and signaling proteins. Bauer et al. therefore specifically overexpressed caveolin-1 (Cav-1) in mouse vascular endothelium to discriminate between the effects of caveolin per se and that of caveolar existence on endothelial cell signaling and angiogenesis. Cav-1 transgenic mice (Cav-1 TG mice), which showed enhanced expression of both endothelial Cav-1 and Cav-2, showed no increase in caveolae number compared with that in wild-type mice; however, they displayed impaired endothelial nitric oxide synthase (eNOS) signaling. Higher concentrations of acetylcholine were required to dilate aortic rings from Cav-1 TG, and constriction of aortic rings was less responsive to a NOS inhibitor. Vascular endothelial growth factor (VEGF)-stimulated vascular permeability and both ischemia- and VEGF-mediated angiogenesis were attenuated in Cav-1 TG mice, as well as VEGF-mediated phosphorylation of Akt and of eNOS (an Akt substrate). VEGF-mediated phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), however, was enhanced. Thus, the authors conclude that Cav-1 likely exerts direct effects on cell signaling independent of its role in caveolar formation. P. M. Bauer, J. Yu, Y. Chan, R. Hickey, P. N. Bernatchez, R. Looft-Wilson, Y. Huang, F. Giordano, R. V. Stan, W. C. Sessa, Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 102 , 204-209 (2005). [Abstract] [Full Text]