Endothelial primary cilia in areas of disturbed flow are at the base of atherosclerosis


      Atherosclerosis develops in the arterial system at sites of low as well as low and oscillating shear stress. Previously, we demonstrated a shear-related distribution of ciliated endothelial cells in the embryonic cardiovascular system and postulated that the primary cilium is a component of the shear stress sensor, functioning as a signal amplifier. This shear-related distribution is reminiscent of the atherosclerotic predilection sites. Thus, we determined whether a link exists between location and frequency of endothelial primary cilia and atherogenesis. We analyzed endothelial ciliation of the adult aortic arch and common carotid arteries of wild type C57BL/6 and apolipoprotein-E-deficient mice. Primary cilia are located at the atherosclerotic predilection sites, where flow is disturbed, in wild type mice and they occur on and around atherosclerotic lesions in apolipoprotein-E-deficient mice, which have significantly more primary cilia in the aortic arch than wild type mice. In addition, common carotid arteries were challenged for shear stress by application of a restrictive cast, resulting in the presence of primary cilia only at sites of induced low and disturbed shear. In conclusion, these data relate the presence of endothelial primary cilia to regions of atherogenesis, where they increase in number under hyperlipidemia-induced lesion formation. Experimentally induced flow disturbance leads to induction of primary cilia, and subsequently to atherogenesis, which suggests a role for primary cilia in endothelial activation and dysfunction.


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        • Shaaban A.M.
        • Duerinckx A.J.
        Wall shear stress and early atherosclerosis: a review.
        Am J Roentgenol. 2000; 174: 1657-1665
        • Hajra L.
        • Evans A.I.
        • Chen M.
        • Hyduk S.J.
        • Collins T.
        • Cybulsky M.I.
        The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation.
        Proc Natl Acad Sci USA. 2000; 97: 9052-9057
        • Cheng C.
        • de Crom R.
        • van Haperen R.
        • et al.
        The role of shear stress in atherosclerosis: action through gene expression and inflammation?.
        Cell Biochem Biophys. 2004; 41: 279-294
        • Cheng C.
        • van Haperen R.
        • de Waard M.
        • et al.
        Shear stress affects the intracellular distribution of eNOS: direct demonstration by a novel in vivo technique.
        Blood. 2005; 106: 3691-3698
        • Cunningham K.S.
        • Gotlieb A.I.
        The role of shear stress in the pathogenesis of atherosclerosis.
        Lab Invest. 2005; 85: 9-23
        • Van der Heiden K.
        • Groenendijk B.C.W.
        • Hierck B.P.
        • et al.
        Monocilia on chicken embryonic endocardium in low shear stress areas.
        Dev Dyn. 2006; 235: 19-28
        • Praetorius H.A.
        • Spring K.R.
        A physiological view of the primary cilium.
        Annu Rev Physiol. 2005; 67: 515-529
        • Yang J.
        • Adamian M.
        • Li T.S.
        Rootletin interacts with C-Nap1 and may function as a physical linker between the pair of centrioles/basal bodies in cells.
        Mol Biol Cell. 2006; 17: 1033-1040
        • Fuchs E.
        • Karakesisoglou I.
        Bridging cytoskeletal intersections.
        Genes Dev. 2001; 15: 1-14
        • Praetorius H.A.
        • Spring K.R.
        Bending the MDCK cell primary cilium increases intracellular calcium.
        J Membr Biol. 2001; 184: 71-79
        • Poelmann R.E.
        The head-process and the formation of the definitive endoderm in the mouse embryo.
        Anat Embryol. 1981; 162: 41-49
        • McGrath J.
        • Somlo S.
        • Makova S.
        • Tian X.
        • Brueckner M.
        Two populations of node monocilia initiate left-right asymmetry in the mouse.
        Cell. 2003; 114: 61-73
        • Yost H.J.
        Left-right asymmetry: nodal cilia make and catch a wave.
        Curr Biol. 2003; 13: R808-R809
        • Masyuk A.I.
        • Masyuk T.V.
        • Splinter P.L.
        • Huang B.Q.
        • Stroope A.J.
        • Larusso N.F.
        Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling.
        Gastroenterology. 2006; 131: 911-920
        • Iomini C.
        • Tejada K.
        • Mo W.
        • Vaananen H.
        • Piperno G.
        Primary cilia of human endothelial cells disassemble under laminar shear stress.
        J Cell Biol. 2004; 164: 811-817
        • Helmlinger G.
        • Berk B.C.
        • Nerem R.M.
        Pulsatile and steady flow-induced calcium oscillations in single cultured endothelial cells.
        J Vasc Res. 1996; 33: 360-369
        • Groenendijk B.C.W.
        • Hierck B.P.
        • Gittenberger-de Groot A.C.
        • Poelmann R.E.
        Development-related changes in the expression of shear stress responsive genes KLF-2, ET-1, and NOS-3 in the developing cardiovascular system of chicken embryos.
        Dev Dyn. 2004; 230: 57-68
        • Groenendijk B.C.W.
        • Hierck B.P.
        • Vrolijk J.
        • et al.
        Changes in shear stress-related gene expression after experimentally altered venous return in the chicken embryo.
        Circ Res. 2005; 96: 1291-1298
        • Nakashima Y.
        • Plump A.S.
        • Raines E.W.
        • Breslow J.L.
        • Ross R.
        ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree.
        Arterioscler Thromb. 1994; 14: 133-140
        • Passerini A.G.
        • Shi C.Z.
        • Francesco N.M.
        • et al.
        Regional determinants of arterial endothelial phenotype dominate the impact of gender or short-term exposure to a high-fat diet.
        Biochem Biophys Res Commun. 2005; 332: 142-148
        • Cheng C.
        • Tempel D.
        • van Haperen R.
        • et al.
        Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress.
        Circulation. 2006; 113: 2744-2753
        • Piperno G.
        • Fuller M.T.
        Monoclonal-antibodies specific for an acetylated form of alpha-tubulin recognize the antigen in cilia and flagella from a variety of organisms.
        J Cell Biol. 1985; 101: 2085-2094
        • Wheatley D.N.
        • Feilen E.M.
        • Yin Z.
        • Wheatley S.P.
        Primary cilia in cultured mammalian cells: detection with an antibody against detyrosinated alpha-tubulin (Id5) and by electron-microscopy.
        J Submicrosc Cytol Pathol. 1994; 26: 91-102
        • Gundersen H.J.
        • Jensen E.B.
        The efficiency of systematic sampling in stereology and its prediction.
        J Microsc. 1987; 147: 229-263
        • Singla V.
        • Reiter J.F.
        The primary cilium as the cell's antenna: signaling at a sensory organelle.
        Science. 2006; 313: 629-633
        • Haust M.D.
        Endothelial cilia in human aortc atherosclerosic lesions.
        Virchows Arch. 1987; 410: 317-326
        • Bystrevskaya V.B.
        • Lichkun V.V.
        • Antonov A.S.
        • Perov N.A.
        An ultrastructural study of centriolar complexes in adult and embryonic human aortic endothelial cells.
        Tissue Cell. 1988; 20: 493-503
        • Fick G.M.
        • Johnson A.M.
        • Hammond W.S.
        • Gabow P.A.
        Causes of death in autosomal-dominant polycystic kidney disease.
        J Am Soc Nephrol. 1995; 5: 2048-2056
        • Kocaman O.
        • Oflaz H.
        • Yekeler E.
        • et al.
        Endothelial dysfunction and increased carotid intima-media thickness in patients with autosomal dominant polycystic kidney disease.
        Am J Kidney Dis. 2004; 43: 854-860
        • Chandran K.B.
        Flow dynamics in the human aorta.
        J Biomech Eng. 1993; 115: 611-616
        • Steinman D.A.
        • Thomas J.B.
        • Ladak H.M.
        • Milner J.S.
        • Rutt B.K.
        • Spence J.D.
        Reconstruction of carotid bifurcation hemodynamics and wall thickness using computational fluid dynamics and MRI.
        Magn Reson Med. 2002; 47: 149-159
        • Shahcheraghi N.
        • Dwyer H.A.
        • Cheer A.Y.
        • Barakat A.I.
        • Rutaganira T.
        Unsteady and three-dimensional simulation of blood flow in the human aortic arch.
        J Biomech Eng. 2002; 124: 378-387
        • Feintuch A.
        • Ruengsakulrach P.
        • Lin A.
        • et al.
        Hemodynamics in the mouse aortic arch as assessed by MRI, ultrasound, and numerical modeling.
        Am J Physiol Heart Circ Physiol. 2007; 292: H884-H892
        • Suo J.
        • Ferrara D.E.
        • Sorescu D.
        • Guldberg R.E.
        • Taylor W.R.
        • Giddens D.P.
        Hemodynamic shear stresses in mouse aortas: implications for atherogenesis.
        Arterioscler Thromb Vasc Biol. 2007; 27: 346-351
        • Hartley C.J.
        • Reddy A.K.
        • Madala S.
        • et al.
        Hemodynamic changes in apolipoprotein E-knockout mice.
        Am J Physiol Heart Circ Physiol. 2000; 279: H2326-H2334
        • Slager C.J.
        • Wentzel J.J.
        • Gijsen F.J.H.
        • et al.
        The role of shear stress in the destabilization of vulnerable plaques and related therapeutic implications.
        Nat Clin Pract Cardiovasc Med. 2005; 2: 456-464
        • van den Berg B.M.
        • Spaan J.A.E.
        • Rolf T.M.
        • Vink H.
        Atherogenic region and diet diminish glycocalyx dimension and increase intima-to-media ratios at murine carotid artery bifurcation.
        Am J Physiol Heart Circ Physiol. 2006; 290: H915-H920
        • Rabelink T.J.
        • Luscher T.F.
        Endothelial nitric oxide synthase: host defense enzyme of the endothelium?.
        Arterioscler Thromb Vasc Biol. 2006; 26: 267-271