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VASCULAR BIOLOGY
Vascular Physiology Group, Department of Experimental Medical Science, Lund University, Lund, Sweden
Submitted 11 July 2007 ; accepted in final form 30 October 2007
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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hypertrophy; vasoconstriction; vascular smooth muscle; endothelium; nitric oxide
Both pressure-induced myogenic tone and flow-mediated dilatation have been shown to be reduced in Cav-1 knockout (KO) arteries (1, 4, 8). Since pressure and shear stress are likely to be sensed by different mechanisms, involving the endothelium and smooth muscle cells, respectively, it remains to be clarified if both modalities are similarly dependent on caveolae. It should be noted that in a physiological context the two types of stimuli often act together, as, e.g., flow-dependent vasodilatation increases wall tension even if transmural pressure is unchanged.
Using an organ culture of mouse portal veins, we have shown that physiological mechanical stress stimulates the synthesis of smooth muscle differentiation markers via an increase in actin polymerization, mediated by activation of Rho and downstream phosphorylation (inactivation) of the actin-depolymerizing factor cofilin (3, 29). Stretch also stimulates growth of the portal vein via an increase in ERK1/2 phosphorylation, partly depending on an endogenous release of angiotensin II and endothelin-1 (28, 30). Stretch-induced ERK1/2 activation and growth of the portal vein are sensitive to extraction of cholesterol, which disrupts membrane microdomains, such as lipid rafts and caveolae (28). However, the functional role of caveolin and caveolae for stretch signaling at normal cholesterol concentration has not been elucidated.
Evidence exists that the basal level of ERK1/2 activation in vascular smooth muscle cells of Cav-1-deficient mice is increased (11), suggesting that caveolin exerts a negative regulatory effect on mitogenic signaling irrespective of mechanical conditions. This basal ERK activity may, however, be regulated separately from that induced by mechanical stimulation, and, moreover, the effect of other signaling components in the vascular wall, such as the endothelium, will influence the physiological response. The ERK1/2 activation by stretch of the portal vein is independent of the endothelium (28), and hence this model is useful for the investigation of mechanosensitive signals arising from vascular smooth muscle. To account also for the role of the endothelium in mechanosensation, an arterial model is preferable. It has been demonstrated that flow-dependent dilatation is impaired in carotid arteries of Cav-1 KO mice (27), whereas the role of Cav-1 in the response specifically to pressure in this vessel has not been reported. In the present study, we used portal veins and carotid arteries from Cav-1 KO mice to investigate both acute and long-term signaling events in response to physiological stretch and shear stress of the intact vascular wall ex vivo.
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METHODS |
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Protein synthesis.
Protein synthesis was measured by autoradiography following [35S]methionine incorporation in organ culture as previously described (29). Following the incubation with radiolabel (24 h), each portal vein was snap frozen and homogenized in 50 µl Laemmli sample buffer. The protein concentration was then determined in all homogenates using a Bio-Rad protein assay (the extremes were 0.8 and 1.2 mg protein/ml). The volume of homogenate was adjusted so that 5 µg protein was loaded in each well. After separation of the proteins, gels were silver stained. Following the scanning and analysis of protein loading, gels were dried and subjected to autoradiography. Protein loading, as estimated from the optical density (OD) x mm2 over an entire lane on the silver-stained gel, was equal in all samples (stretched WT: 100%; stretched KO: 100.9 ± 1.4%; unstretched WT: 99 ± 2.5%; unstretched KO: 98.9 ± 2.2%; n = 8–9). Global protein synthesis was defined as the OD x mm2 measured over all bands in one lane on the autoradiograph. Some bands, such as smooth muscle protein 22 (SM22), actin, and desmin, incorporate more radiolabel in stretched versus unstretched veins. This reflects proteins whose synthesis is specifically affected by mechanical stimulation. To illustrate the effect of stretch on synthesis of specific proteins, the change in OD along one lane representing an unstretched vein was subtracted from that of a stretched vein on the same autoradiograph (cf. 
Fig. 4).
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/β (no. 610406, clone 2297, BD Biosciences) were used. Bands were visualized using ECL (Pierce West Femto). Force measurement. Portal veins were attached to force transducers (AE 801, SensoNor A/S), stretched to 3 mN, and equilibrated in HEPES buffer [composed of (in mM) 135.5 NaCl, 5.9 KCl, 2.5 CaCl2, 1.2 MgCl2, 11.6 glucose, and 11.6 HEPES; pH 7.4] for 1 h. They were then contracted with HEPES buffer containing 60 mM KCl. Integrated force over 5 min was calculated, and the mean of two contractions was used for the evaluation of active force. Rho kinase was inhibited using Y-27632 (10 µM, Calbiochem) for 15 min. The cross-sectional area was determined from wet weight divided by length at 3 mN.
Carotid arteries.
Carotid arteries were dissected, mounted on a glass pipette, and ligated at the free end. Following 1 h of equilibration in HEPES buffer, intraluminal pressure was increased to 120 mmHg for 1 h, with the contralateral artery kept at 0 mmHg. Left and right carotid arteries were randomized. For flow experiments, arteries were not ligated, and, following the equilibration period, intraluminal flow (440 µl/min) was delivered by a peristaltic pump to one artery of each pair for 15 min. In separate arteries fixed for histology, lumen diameter was calculated from the internal circumference (WT: 288 ± 14 µm and KO: 320 ± 12 µm; n = 5). Shear stress was calculated as follows: SS = 4µQ/
r3, where SS is shear stress, µ is viscosity (0.007 Poise), Q is flow (in cm3/s), and r is radius (in cm). Using the above values, shear stress was 
19 dyn/cm2. Following flow or pressure experiments, arteries were quickly frozen for analysis by Western blot.
Statistics. Values are presented as means ± SE. Student's t-test was used for the evaluation of statistical significance. For multiple comparisons, one-way ANOVA followed by the Bonferroni post hoc test was used. P < 0.05 was considered as statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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(amino acids 1–178). The lower band likely represents Cav-1β (amino acids 32–178). Portal veins and carotid arteries from KO mice lacked both bands (Fig. 1A). In vascular smooth muscle of KO mice, Cav-2 is also largely absent, Cav-3 is substantially reduced, and no caveolae structures are observed (4, 24). We have previously reported that physiological stretch stimulates protein synthesis in the portal vein and that activation of ERK1/2 is a mediator of this effect (3, 30). ERK1/2 activation is rapid and transient with a peak at about 5 min following the onset of stretch, correlating with rapid activation of FAK (2). Stretched portal veins had a two- to threefold increase in ERK1/2 phosphorylation compared with unstretched veins. This response was not affected by ablation of Cav-1 (Fig. 1B). Similarly, FAK phosphorylation by 5 min of stretch was unaffected by ablation of Cav-1 (Fig. 1C). Other signaling proteins tested in this study, i.e., cofilin and Akt, were not affected by 5-min stretch of portal veins from either KO or WT mice. Excessive nitric oxide (NO) production is an important phenotype of Cav-1-deficient mice (5). However, the role of endothelial NO production in the portal vein is uncertain (9, 13). To investigate possible effects of endogenous NO on smooth muscle signaling, portal veins were incubated with N-nitro-L-arginine methyl ester (L-NAME; 300 µM) for 1 h and then stretched for 5 min. In WT mice, L-NAME significantly reduced Akt phosphorylation in stretched portal veins, whereas no such effect was observed in KO mice (Fig. 1D). Phosphorylation of either FAK or ERK1/2 was unaffected by NO synthase (NOS) inhibition (data not shown).
Effects of long-term stretch. Long-term stretch (24–72 h) causes increased growth and global protein synthesis as well as Rho activation and contractile differentiation compared with unstretched portal veins (3). After 72 h in organ culture, ERK1/2 and Akt phosphorylation levels no longer differed between stretched and unstretched portal veins (Fig. 2, A and B). However, both ERK1/2 and Akt phosphorylation were higher in KO portal veins than in WT portal veins at 72 h. FAK phosphorylation, phosphorylated cofilin, and total cofilin contents were all increased in stretched versus unstretched portal veins but did not differ between KO and WT vessels (Fig. 2, C–E). Since cofilin expression was increased in stretched vessels, the summarized data were separated into two graphs to display phosphorylated and total cofilin contents, respectively.
Effect of organ culture and stretch on ERK phosphorylation and Cav-1 protein content. The stoichiometry of ERK phosphorylation is higher at 5 min compared with 72 h of organ culture (2). To address if this difference correlates with altered expression of Cav-1, we determined Cav-1 content in WT portal veins at 5 min and 72 h in the presence and absence of stretch. ERK1/2 phosphorylation was assessed in the same preparations, and a reference sample was used for normalization between blots. As expected, ERK1/2 phosphorylation was highest at 5 min with a marked difference between stretched and unstretched preparations. At 72 h, ERK1/2 phosphorylation was considerably lower, and no stretch-dependent difference was seen (Fig. 3A). Cav-1 expression was significantly reduced at 72 h compared with 5 min, and no stretch-dependent effect on expression was evident (Fig. 3B). This argues that ERK1/2 phosphorylation differs between genotypes only when the level is near basal (72 h) and that the decline in stoichiometry of ERK phosphorylation between 5 min and 72 h is not due to an increasing inhibitory influence of Cav-1.
Stretch-induced protein synthesis. It has previously been observed that stretch of the portal vein increases both global and smooth muscle-specific protein synthesis. To investigate the role of Cav-1 in this response, we determined [35S]methionine incorporation during organ culture by autoradiography, as shown in Fig. 4A. As previously reported (3, 29), stretched portal veins showed increased incorporation into a number of bands representing smooth muscle differentiation marker proteins. Particularly evident were SM22, desmin, actin, and tropomyosin, which are shown in Fig. 4A. These bands were labeled on the basis of molecular weight, stretch sensitivity, and earlier identification by Western blot and/or matrix-assisted laser desorption/ionization-time of flight analysis (3, 29). Summarized data for SM22 and desmin are shown in Fig. 4, C and D. Total radioactivity integrated over the whole lanes, representing global protein synthesis (15–300 kDa), was higher in stretched versus unstretched veins (Fig. 4B). No effect of Cav-1 ablation was seen in the stretch dependence of either global protein synthesis or specific synthesis of SM22 and desmin. However, global protein synthesis in both stretched and unstretched portal veins from KO mice was slightly but significantly greater than in the corresponding WT vessels.
Contractility and cross-sectional area. The contractile response of freshly dissected portal veins to depolarization by 60 mM K+ did not differ between KO and WT mice (Fig. 5A; force: 1.0 ± 0.14 mN in WT vs. 0.96 ± 0.10 mN in KO). An increased cross-sectional area of the portal vein in KO mice was observed (Fig. 5B), but active stress did not differ significantly (Fig. 5C). The contractile response was greatly inhibited by Y-27632, a specific inhibitor of Rho-associated kinase, suggesting that the Ca2+ sensitivity of the contractile system is a major determinant of the force response to membrane depolarization. The relative dependence on Ca2+ sensitization was not different between KO and WT (Fig. 5C; force: 0.18 ± 0.02 mN in WT vs. 0.18 ± 0.03 mN in KO).
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19 dyn/cm2 for 15 min following a 1-h preincubation in the absence of flow. As shown in Fig. 6E, flow caused an increase in Akt phosphorylation in WT carotid arteries, which was absent in KO carotid arteries. There was no significant effect of flow on ERK1/2 phosphorylation under these conditions (Fig. 6F). |
DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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In a previous study, we observed that acute (10 min) stretch of rat portal veins causes tyrosine phosphorylation of proteins in membrane domains containing Cav-1 and that cholesterol depletion by methyl-β-cyclodextrin inhibits early stretch-induced ERK1/2 phosphorylation and stretch-dependent global protein synthesis (28). The difference between these results and the findings in Cav-1 KO vessels (present study) are likely due to the persistence of lipid rafts in Cav-1 KO vessels even though caveolae are eliminated in both cases. ERK1/2 has been shown to exist in caveolae-free membrane regions, whereas its activation via growth factor signaling may depend on caveolae (10). Possibly stretch-induced ERK activation requires lipid rafts but not necessarily Cav-1.
In jugular veins exposed to arterial pressure and flow in vivo for 15 min, ERK1/2 and Akt phosphorylation were dramatically increased in WT mice but not KO mice (23). In this model, the venous endothelium will be affected by a greatly increased shear stress, and the vessel wall is extensively stretched by the elevated pressure, triggering a repair response, as shown by the subsequent neointima formation in the transplanted vein (23). Neointima formation can be reduced by external protection of the transplanted vessel, which suggests that excessive mechanical stretch is an important stimulus for neointimal growth (14).
In the present in vitro study, carotid arteries were exposed to flow for 15 min without simultaneous pressurization. Akt phosphorylation was increased by flow in WT but not Cav-1 KO vessels, but there was no effect of flow on ERK1/2 phosphorylation in either genotype. In response to pressure without flow, there was no effect on Akt phosphorylation, and the ERK response was unaffected by Cav-1 ablation. Thus, mechanically induced Akt but not ERK phosphorylation was found to depend on Cav-1.
Shear stress has been shown to increase both MAPK and Akt phosphorylation in cultured endothelial cells (7, 20), but, interestingly, preconditioning of cells with shear stress for 6 h increases caveolin expression and concomitantly eliminates flow-induced ERK1/2 phosphorylation (21). The endothelial cells in the carotid arteries used in this study are preconditioned to shear stress since they have been exposed to blood flow in vivo. This may be the reason why these cells do not respond to shear stress with increased MAPK activity, whereas the situation is different in damaged or phenotypically modified endothelium.
Both caveolae and caveolin have been implicated in flow-induced endothelial NO production via the regulation of endothelial NOS activity by PI3K-Akt signaling (21, 23, 27). In addition, studies have shown that NO promotes Akt phosphorylation via cGMP production in vascular smooth muscle cells (26), which could provide a link between shear stress on the endothelium and Akt phosphorylation in smooth muscle. Abolishing NO production by L-NAME caused decreased Akt phosphorylation in WT but not KO portal veins, despite a probably higher NO production in KO portal veins. This result suggests that Akt signaling in smooth muscle is impaired in KO mice. The abolished Akt response to flow in KO carotid arteries may thus result from impaired regulation of NO production in the endothelium, but, in addition, an impaired response to NO in smooth muscle cells may contribute. Although the vast majority of cells in the carotid arteries and portal vein are of smooth muscle origin, we cannot exclude an influence of other cell types, such as endothelial cells, on Western blot data.
Stretch of the portal vein causes phosphorylation of cofilin, thereby inhibiting its activity and promoting actin filament stability (3). Levels of cofilin phosphorylation following organ culture were similar in stretched WT and KO portal veins and were reduced to <50% in the absence of stretch in both genotypes. Expression of the cofilin gene is, like SM22 and desmin, regulated by myocardin and serum response factor (25), and the protein level of cofilin is therefore sensitive to mechanical stretch (3). Furthermore, the Rho kinase inhibitor Y-27632 had similar effects on contractile responses in depolarized WT and KO portal veins. These results suggest that the Rho pathway, upstream of Rho kinase and cofilin, can be activated to a similar extent in the KO portal vein as in the WT portal vein by stretch or contractile stimulation. In rat mesenteric resistance arteries, pressure-induced membrane translocation of RhoA and binding to Cav-1 have been demonstrated (8). The effects of Cav-1 ablation on RhoA translocation and activation were, however, not investigated.
Increased basal ERK1/2 and Akt phosphorylation in KO relative to WT portal veins correlate with increased global protein synthesis. Several growth factor receptors and intracellular signaling molecules have been shown to be negatively regulated by Cav-1. These include c-Src, H-Ras, MAPKs, and receptor tyrosine kinases (6, 16). On the other hand, Patel et al. (19) recently demonstrated a positive correlation between Cav-1 expression and proliferation in human pulmonary artery smooth muscle cells. These divergent results suggest that the influence of caveolae on growth may depend on the repertoire of signaling proteins expressed in the cells/tissues under study.
The transient increase in ERK1/2 phosphorylation following stretch of the portal vein was shown to be unaffected by Cav-1 ablation. During the following organ culture, ERK phosphorylation in stretched veins declined to a level at 72 h of <10% of the value at 5 min after stretch. At this time point, ERK phosphorylation no longer differed between stretched and unstretched vessels but was 25% higher in Cav-1 KO veins than in WT veins. A difference of this absolute magnitude would probably not be detectable on top of the phosphorylation at 5 min after stretch and, hence, cannot be excluded. The reason for the decline in the level of ERK phosphorylation during the course of organ culture, which is found also in the rat portal vein (30), is unclear, but one possible explanation is reorganization of the actin cytoskeleton to accommodate the applied force and normalize tissue stress (2). Differing contents of Cav-1 following culture could not explain this decrease. We conclude that, whereas basal ERK1/2 phosphorylation is elevated in vessels from Cav-1 KO mice, the stretch-sensitive component of ERK phosphorylation is unaffected by Cav-1 depletion.
In a detailed functional and morphometric analysis, we have shown that mesenteric resistance arteries in Cav-1 KO mice are remodeled with an increased media-to-lumen ratio, which compensates for decreased myogenic tone to uphold normal arterial pressure (4). While the remodeling to a degree may be explained by increased basal ERK1/2 and Akt activity in Cav-1 KO mice, the present results show that increased wall stress can lead to growth of the vascular wall in the absence of Cav-1. Indeed, wall tension is expected to be increased in Cav-1 KO mice during development if there is vascular dilatation without a matching reduction in blood pressure. Remodeling as a result of altered wall stress consequent upon endothelium-dependent dilatation is supported by a recent report (17) showing that expression of caveolin selectively in the endothelium of Cav-1 KO mice prevents hypertrophic remodeling of the smooth muscle.
In conclusion, although chronic compensation cannot be ruled out, stretch sensitivity of FAK, ERK1/2, and cofilin phosphorylation, as well as of synthesis rates for both total and smooth muscle-specific proteins, is retained in Cav-1 KO mice and thus not critically dependent on Cav-1. Whereas Akt phosphorylation does not respond to stretch or pressure, it is activated by flow in the carotid artery of WT mice but not KO mice. Since stretch is an essential stimulus for the activation of smooth muscle myogenesis and gene expression (12), the essentially normal development of the vascular tree in Cav-1 KO mice would have been unlikely unless signals for growth and differentiation retain their stretch sensitivity, as demonstrated here.
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GRANTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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