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. 2006 May;116(5):1284-91.
doi: 10.1172/JCI27100.

Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels

Jun Yu  1 , Sonia Bergaya, Takahisa Murata, Ilkay F Alp, Michael P Bauer, Michelle I Lin, Marek Drab, Teymuras V Kurzchalia, Radu V Stan, William C Sessa
Affiliations

Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels

Jun Yu et al. J Clin Invest. 2006 May.

Abstract

Caveolae in endothelial cells have been implicated as plasma membrane microdomains that sense or transduce hemodynamic changes into biochemical signals that regulate vascular function. Therefore we compared long- and short-term flow-mediated mechanotransduction in vessels from WT mice, caveolin-1 knockout (Cav-1 KO) mice, and Cav-1 KO mice reconstituted with a transgene expressing Cav-1 specifically in endothelial cells (Cav-1 RC mice). Arterial remodeling during chronic changes in flow and shear stress were initially examined in these mice. Ligation of the left external carotid for 14 days to lower blood flow in the common carotid artery reduced the lumen diameter of carotid arteries from WT and Cav-1 RC mice. In Cav-1 KO mice, the decrease in blood flow did not reduce the lumen diameter but paradoxically increased wall thickness and cellular proliferation. In addition, in isolated pressurized carotid arteries, flow-mediated dilation was markedly reduced in Cav-1 KO arteries compared with those of WT mice. This impairment in response to flow was rescued by reconstituting Cav-1 into the endothelium. In conclusion, these results showed that endothelial Cav-1 and caveolae are necessary for both rapid and long-term mechanotransduction in intact blood vessels.

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Figures

Figure 1
Figure 1. Characterization of carotid arteries from WT, Cav-1 KO, and Cav-1 RC mice.
(A) PCR genotyping from genomic DNA extracted from tails of WT (lower band, endogenous murine Cav-1), Cav-1 KO (upper band, neomycine cassette), and Cav-1 RC mice (middle band, canine Cav-1 transgene). 1 kb plus, DNA Mw ladder. (B) Protein levels of eNOS, Cav-1, and Cav-2 in 4 pooled carotid arteries. hsp90 was used as a loading control. (C) In situ whole-mount immunostaining performed in WT, Cav-1 KO, and Cav-1 RC carotid arteries showed expression of Cav-1 protein (red) and endothelial cell marker PECAM-1 protein (green). (D) Representative transmission electron micrographs performed in carotid arteries from WT, Cav-1 KO, and Cav-1 RC mice. Arrows indicate the presence of caveolae. C and D are representative of 4 experiments.
Figure 2
Figure 2. Cav-1 is necessary for chronic flow-induced remodeling in vivo, an effect rescued by reconstitution of Cav-1 in the endothelium.
After 2 weeks of external carotid arterial ligation, morphometric analysis was performed in perfusion-fixed RCAs and LCAs from WT (n = 6), Cav-1 KO (n = 11), and Cav-1 RC (n = 9) mice. (A) Morphometric analysis showed a reduction in the lumen diameter of LCAs compared with contralateral RCAs in WT and Cav-1 RC mice, with no changes in lumen diameter in Cav-1 KO mice, in response to a reduced flow remodeling stimulus. Wall thickness remained constant in remodeled LCAs from WT and Cav-1 RC mice, whereas wall thickness increased in LCAs of Cav-1 KO mice. (B and C) Representative images of H&E- (B) or trichrome-stained (C) cross sections of LCAs isolated from WT, Cav-1 KO, and Cav-1 RC mice showed obvious increased wall thickness in remodeled Cav-1 KO arteries. Magnification, ×400. (D) Increased BrdU incorporation into remodeled LCAs from Cav-1 KO mice. Values are mean ± SEM. *P < 0.05, 1-way ANOVA with Bonferroni post test.
Figure 3
Figure 3. Cav-1 is necessary for flow-induced vasodilation, an effect rescued by reconstitution of Cav-1 in the endothelium.
(A) Flow-induced dilations were observed in pressurized isolated carotid arteries from WT (n = 10), Cav-1 KO (n = 8), and Cav-1 RC mice (n = 6). Increases in lumen diameter were expressed as a function of flow rate. The flow-induced dilation was impaired in Cav-1 KO mice compared with WT and Cav-1 RC mice. (B) Increases in lumen diameter (from the same experiments as in A) were expressed as a function of shear stress (measured as dyn/cm2, where 1 dyn = 1 g/cm/s2). (C) Ach-induced dilations were examined after Phe contraction in pressurized isolated carotid arteries from WT (n = 6), Cav-1 KO (n = 9), and Cav-1 RC mice (n = 3). (D) Ach-induced dilations, expressed as percent relaxation of the Phe contraction, were examined in carotid rings from WT (n = 4), Cav-1 KO (n = 4), and Cav-1 RC mice (n = 4) mounted in a wire myograph under isometric conditions. Values are mean ± SEM. *P < 0.05, 2-way ANOVA with Bonferroni post test.
Figure 4
Figure 4. Cav-1 is necessary for flow-induced eNOS activation.
(A–D) Flow-induced dilations in pressurized isolated carotid arteries in the absence (circles) and presence (triangles) of l-NAME from WT (A; filled symbols; n = 4 and 10 with and without l-NAME, respectively), Cav-1 KO (B; open symbols; n = 4 and 8 with and without l-NAME, respectively), and Cav-1 RC mice (C; gray symbols; n = 4 and 6 with and without l-NAME, respectively). (D) Comparison of flow-induced dilation performed in the presence of l-NAME between the 3 strains (n = 4 per group). The responses to flow were similar between all groups of mice in the presence of L-NAME. *P < 0.05. (E) Basal eNOS phosphorylation on serine 1176 was reduced in Cav-1 KO mice and rescued in Cav-1 RC mice. Carotid arterial lysates were prepared as described in Methods, and densitometric evaluation of the normalized ratio of phosphorylated eNOS to total eNOS is shown below. (F) The localization of eNOS in intact carotid arteries was similar in WT, Cav-1 KO, and Cav-1 RC mice. Arrow reflects the direction of flow through the vessel segment.
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