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      Membrane Cholesterol Depletion with β-Cyclodextrin Impairs Pressure-Induced Contraction and Calcium Signalling in Isolated Skeletal Muscle Arterioles

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          Objective: Given evidence for clustering of signalling molecules and ion channels in cholesterol-rich membrane domains, the involvement of such structures in arteriolar smooth muscle mechanotransduction was examined. Method: To determine the contribution of smooth muscle cholesterol-rich membrane domains to the myogenic response, isolated arterioles were exposed to the cholesterol-depleting agent β-cyclodextrin (1–10 m M) in the absence and presence of excess exogenous cholesterol. Results: β-Cyclodextrin significantly impaired pressure-induced vasoconstriction, while excess cholesterol attenuated this effect. Impaired myogenic constriction was evident in de-endothelialized vessels, indicating an action at the level of smooth muscle. β-Cyclodextrin treatment uncoupled increases in intracellular Ca<sup>2+</sup> from myogenic constriction and depleted intracellular Ca<sup>2+</sup> stores consistent with a loss of connectivity between plasma membrane and sarcoplasmic reticulum signalling. However, β-cyclodextrin-treated arterioles showed unaltered constrictor responses to KCl and phenylephrine. Electron microscopy verified that β-cyclodextrin caused a decrease in caveolae, while confirmation of smooth muscle containing caveolae was obtained by immunostaining for caveolin-1. Viability of β-cyclodextrin-treated arterioles was confirmed by agonist sensitivity and propidium iodide nuclear staining. Conclusion: The data suggest that smooth muscle cholesterol-rich membrane domains contribute to the myogenic response. Further studies are required to determine whether this relates to specific mechanosensory events or generalized alterations in membrane function.

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          Most cited references 23

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          Role of caveolae and caveolins in health and disease.

          Although they were discovered more than 50 years ago, caveolae have remained enigmatic plasmalemmal organelles. With their characteristic "flasklike" shape and virtually ubiquitous tissue distribution, these interesting structures have been implicated in a wide range of cellular functions. Similar to clathrin-coated pits, caveolae function as macromolecular vesicular transporters, while their unique lipid composition classifies them as plasma membrane lipid rafts, structures enriched in a variety of signaling molecules. The caveolin proteins (caveolin-1, -2, and -3) serve as the structural components of caveolae, while also functioning as scaffolding proteins, capable of recruiting numerous signaling molecules to caveolae, as well as regulating their activity. That so many signaling molecules and signaling cascades are regulated by an interaction with the caveolins provides a paradigm by which numerous disease processes may be affected by ablation or mutation of these proteins. Indeed, studies in caveolin-deficient mice have implicated these structures in a host of human diseases, including diabetes, cancer, cardiovascular disease, atherosclerosis, pulmonary fibrosis, and a variety of degenerative muscular dystrophies. In this review, we provide an in depth summary regarding the mechanisms by which caveolae and caveolins participate in human disease processes.
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            Regulation of arterial diameter and wall [Ca2+] in cerebral arteries of rat by membrane potential and intravascular pressure.

            1. The regulation of intracellular [Ca2+] in the smooth muscle cells in the wall of small pressurized cerebral arteries (100-200 micron) of rat was studied using simultaneous digital fluorescence video imaging of arterial diameter and wall [Ca2+], combined with microelectrode measurements of arterial membrane potential. 2. Elevation of intravascular pressure (from 10 to 100 mmHg) caused a membrane depolarization from -63 +/- 1 to -36 +/- 2 mV, increased arterial wall [Ca2+] from 119 +/- 10 to 245 +/- 9 nM, and constricted the arteries from 208 +/- 10 micron (fully dilated, Ca2+ free) to 116 +/- 7 micron or by 45 % ('myogenic tone'). 3. Pressure-induced increases in arterial wall [Ca2+] and vasoconstriction were blocked by inhibitors of voltage-dependent Ca2+ channels (diltiazem and nisoldipine) or to the same extent by removal of external Ca2+. 4. At a steady pressure (i.e. under isobaric conditions at 60 mmHg), the membrane potential was stable at -45 +/- 1 mV, intracellular [Ca2+] was 190 +/- 10 nM, and arteries were constricted by 41 % (to 115 +/- 7 micron from 196 +/- 8 micron fully dilated). Under this condition of -45 +/- 5 mV at 60 mmHg, the voltage sensitivity of wall [Ca2+] and diameter were 7.5 nM mV-1 and 7.5 micron mV-1, respectively, resulting in a Ca2+ sensitivity of diameter of 1 mum nM-1. 5. Membrane potential depolarization from -58 to -23 mV caused pressurized arteries (to 60 mmHg) to constrict over their entire working range, i.e. from maximally dilated to constricted. This depolarization was associated with an elevation of arterial wall [Ca2+] from 124 +/- 7 to 347 +/- 12 nM. These increases in arterial wall [Ca2+] and vasoconstriction were blocked by L-type voltage-dependent Ca2+ channel inhibitors. 6. The relationship between arterial wall [Ca2+] and membrane potential was not significantly different under isobaric (60 mmHg) and non-isobaric conditions (10-100 mmHg), suggesting that intravascular pressure regulates arterial wall [Ca2+] through changes in membrane potential. 7. The results are consistent with the idea that intravascular pressure causes membrane potential depolarization, which opens voltage-dependent Ca2+ channels, acting as 'voltage sensors', thus increasing Ca2+ entry and arterial wall [Ca2+], which leads to vasoconstriction.
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              Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels.

              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.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                June 2007
                30 March 2007
                : 44
                : 4
                : 292-302
                aMicrovascular Biology Group, School of Medical Sciences, RMIT University, Bundoora, and bDepartment of Physiology and Pharmacology, University of New South Wales, Kensington, Australia; cDalton Cardiovascular Research Institute and Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Mo., USA
                101451 J Vasc Res 2007;44:292–302
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 43, Pages: 11
                Research Paper


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