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. 2009 Jul;10(1):48-54.
doi: 10.1016/j.cmet.2009.06.003.

Genetic evidence supporting a critical role of endothelial caveolin-1 during the progression of atherosclerosis

Carlos Fernández-Hernando  1 , Jun Yu, Yajaira Suárez, Christoph Rahner, Alberto Dávalos, Miguel A Lasunción, William C Sessa
Affiliations

Genetic evidence supporting a critical role of endothelial caveolin-1 during the progression of atherosclerosis

Carlos Fernández-Hernando et al. Cell Metab. 2009 Jul.

Abstract

The accumulation of LDL-derived cholesterol in the artery wall is the initiating event that causes atherosclerosis. However, the mechanisms that lead to the initiation of atherosclerosis are still poorly understood. Here, by using endothelial cell-specific transgenesis of the caveolin-1 (Cav-1) gene in mice, we show the critical role of Cav-1 in promoting atherogenesis. Mice were generated lacking Cav-1 and apoE but expressing endothelial-specific Cav-1 in the double knockout background. Genetic ablation of Cav-1 on an apoE knockout background inhibits the progression of atherosclerosis, while re-expression of Cav-1 in the endothelium promotes lesion expansion. Mechanistically, the loss of Cav-1 reduces LDL infiltration into the artery wall, promotes nitric oxide production, and reduces the expression of leukocyte adhesion molecules, effects completely reversed in transgenic mice. In summary, this unique model provides physiological evidence supporting the important role of endothelial Cav-1 expression in regulating the entry of LDL into the vessel wall and the initiation of atherosclerosis.

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Figures

Fig 1
Fig 1. Characterization of Cav-1 expression in arteries from ApoE−/−, ApoE−/− Cav-1−/− and ApoE−/−Cav-1Recmice
(a). Cav-1 is present in EC and VSM in atherosclerotic vessels from apoE−/− mice. Representative histological analysis of cross-sections from the aoric sinus in phase contrast and co-stained with CD31 (endothelial marker), αSMC actin (vascular smooth muscle marker) and CD68 (macrophage marker). (b). Protein levels of eNOS, Cav-1 and Cav-2 from mouse aorta. Hsp90 was used as a loading control. (c). Immunostaining for Cav-1 in vessels from ApoE−/−, ApoE−/− Cav-1−/− and ApoE−/−Cav-1Rec mice showing the expression of endothelial marker CD31 (red) and Cav-1 protein (green). The scale bars represent 100 µm
Fig 2
Fig 2. Endothelial-specific expression of Cav-1 is critical for the progression of atherosclerosis
(a). Representative examples of light microscopic images from ApoE−/−, ApoE−/− Cav-1−/− and ApoE−/− Cav-1Rec aortic arches. Atherosclerotic plaques are easily visualized by the white areas inside the arteries. The arrows indicate the innominate artery (1), left carotid artery (2) and left subclavian artery (3). (b). Oil red O staining of aortas from mice with the indicated genotypes. Atheroma formation was significantly reduced in ApoE−/− Cav-1−/− mice (n=9) compared to ApoE−/− mice (n=22). Re-expression of Cav-1 in the endothelium (ApoE−/− Cav-1Rec, n=10) promotes plaque formation in the doubly mutant mice. (c). Representative histological analysis of aortic sinus stained with hematoxylin and eosin, and Oil red O from the indicated genotypes (n=6). The scale bars represent 200 µm
Fig 3
Fig 3. Endothelial-specific Cav-1 regulates LDL entry into the artery wall and the NO production in EC
(a). Immunofluorescence analysis of Di-LDL infiltration in different aortic segments. En face fluorescence images of aortic sections from 6-week- old ApoE−/− old mice 30 min after intravenous injection with DiI-LDL. The images were captured using a 40X objective. (b). En face fluorescence images of aortic sections from 6 week old ApoE−/−, ApoE−/−Cav-1−/− and ApoE−/−Cav-1Rec old mice 30 min after intravenous injection with DiI-LDL. (c) Quantification of DiI fluorescence intensity from en face images. The data are quantified as fluorescence-positive area versus total area. The data represent the mean ± SEM; n=5 mice in each group. * Indicates p< 0.05 compared with ApoE−/−. The images were captured using a 10X objective. (d) NO release from wt, Cav-1−/− and Cav-1Rec. The nitrite accumulation was quantified for 8 h. The date represents the mean ± SEM of triplicate samples repeated in three independent experiments. * Indicates p< 0.05 compared with control.
Fig 4
Fig 4. Loss of Cav-1 alters the expression profile of atherosclerosis-related genes and macrophage content in the artery wall
(a) Expression profile of atherosclerosis-related genes assessed by real-time PCR. Five independent qPCR reactions were carried out for each condition with iCycler (BioRad). The n-fold change for each gene, after diet compared to before diet was calculated. The data represents the mean ±SEM of quintuplicate samples. Black bars correspond to ApoE−/−, white bars to ApoE−/−Cav-1−/− and grey bars to ApoE−/−Cav-1Rec mice. (b) Western Blot analyses (left panel) and densitometry (right panel) of VCAM-1, ICAM-1, CD68, eNOS, pAkt-473, Akt, Actin, HSP-90 and Cav-1 in aortic extracts prepared ApoE−/−, ApoE−/−Cav-1−/− and ApoE−/−Cav-1Rec mice fed a high cholesterol diet for 12 weeks. Results for four representative mice are shown for each genotype. The data represent the mean ± SEM of quadruplicate samples. (c). CD68-positive macrophages in lesions from ApoE−/−, ApoE−/−Cav-1−/− and ApoE−/−Cav-1Rec mice after 12 weeks of a high cholesterol diet were detected by CD68 staining. The data are quantified as CD68-positive area versus total lesion area (right panel). The data represent the mean ± SEM; n=5 in each group.
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