Endothelial Cilia Are Fluid Shear Sensors That Regulate Calcium Signaling and Nitric Oxide Production Through Polycystin-1

Nauli, Surya M.; Kawanabe, Yoshifumi; Kaminski, John J.; Pearce, William J.; Ingber, Donald E.; Zhou, Jing

doi:10.1161/circulationaha.107.710111

Cited by 402 publications

(437 citation statements)

References 36 publications

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“…The recently published data on the role of polycystin-1 in the cilium and its role in the immediate response to shear stress (Nauli et al, 2008) confirms our data on the important role for the primary cilium in endothelial mechanosensing . We also show that non-ciliated cells still retain the capacity for a significant and prolonged response to fluid shear stress.…”

Section: Discussionsupporting

confidence: 91%

“…In addition, it can provide cells with directional information about blood flow to which EC respond with reorientation to the local shear axis (Topper and Gimbrone, 1999;Noria et al, 2004). Mechanical deformation of the cytoskeleton also links the apparently non-related shear sensors that have been described to date, including integrins, cell-cell adhesion molecules, tyrosine kinase receptors, G protein-coupled receptors, and ion channels for Ca 2ϩ and K ϩ (Lehoux et al, 2006;Li et al, 2005;Nauli et al, 2008). All these proteins are connected to the cytoskeleton, either directly or through linker proteins.…”

Section: Discussionmentioning

confidence: 99%

“…These sensory membrane extensions are exclusively present on EC in areas of low and disturbed blood flow, in the embryo as well as in the adult , which suggests a role in signal amplification of the fluid shear forces into the cell. In addition, recent evidence shows a role for the endothelial cilium in functional localization of polycystin-1 and mediation of the acute response, i.e., an intracellular calcium transient, to shear stress (Nauli et al, 2008). However, EC in high shear areas lack primary cilia, but are still responsive to fluid forces.…”

Section: Discussionmentioning

confidence: 99%

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Primary cilia sensitize endothelial cells for fluid shear stress

Hierck

Heiden

Alkemade

et al. 2008

Developmental Dynamics

155

108

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Primary cilia are mechanosensors for fluid shear stress, and are involved in a number of syndromes and congenital anomalies. We identified endothelial cilia in areas of low shear stress in the embryonic heart. The objective of the present study was to demonstrate the role of primary cilia in mechanosensing. Ciliated embryonic endothelial cells were cultured from the heart, and non-ciliated cells from the arteries. Nonciliated cells that were subjected to fluid shear stress showed significantly less induction of the shear marker Krü ppel-Like Factor-2, as compared to ciliated cells. In addition, ciliated cells from which the cilia were chemically removed show a similar decrease in flow response. This shows that primary cilia sensitize endothelial cells for fluid shear stress. In addition, we targeted and stabilized the connection of the cilium to the cytoplasm by treatment with Colchicine and Taxol/Paclitaxel, respectively, and show that microtubular integrity is essential to sense shear stress. Developmental Dynamics 237:725-735, 2008.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Primary cilia sensitize endothelial cells for fluid shear stress

Hierck

Heiden

Alkemade

et al. 2008

Developmental Dynamics

155

108

View full text Add to dashboard Cite

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“…38,39 PC1 and PC2 are necessary for the calcium response and nitric oxide release in endothelial cells in response to blood flow. 40 Extracellular flow-induced calcium influx leads to Ca 2+ release from the endoplasmic reticulum via ryanodine and inositol triphosphate receptors, resulting in AMP release. 41 Kidney epithelial cells respond to urinary flow in the lumen of the renal tubules by bending of the PC, which acts as a mechanosensory antenna, increasing membrane permeability to Ca 2+ associated with the generated shear stress on the tubule lining cells, and, therefore, regulating the intracellular calcium response.…”

Section: Cilium: Structure and Signalingmentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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“…TRPP1/TRPP2, TRPV4, TRPC3 and TRPM7 have been localized in endothelial cells and/or smooth muscle cells. They have been reported to be mechanosensors responding to shear stress [10][11][12][13].…”

Section: The Vascular Mechano-sensitive Trp Channelsmentioning

confidence: 99%

Vascular Responses to Shear Stress: The Involvement of Mechanosensors in Endothelial Cells

Ngai¹

2012

TOCVJ

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Shear stress, the frictional drag on the endothelium from blood flow, is a major determinant of vascular physiology and pathology. Due to the pulsatile nature of blood flow, blood vessels are subjected to significant variations in mechanical forces. Endothelial cells situated at the interface between blood and the vessel wall play a crucial role in detecting and responding to the mechanical forces generated by shear stress. Multiple sensing mechanisms are used by endothelial cells to detect changes in mechanical forces, leading to the activation of signaling networks. This review attempts to bring together recent findings on the mechanosensors present in the endothelial cells, and the regulation of endothelium-derived vasoactive autacoid production by shear stress.

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Endothelial Cilia Are Fluid Shear Sensors That Regulate Calcium Signaling and Nitric Oxide Production Through Polycystin-1

Cited by 402 publications

References 36 publications

Primary cilia sensitize endothelial cells for fluid shear stress

Primary cilia sensitize endothelial cells for fluid shear stress

Autophagy and regulation of cilia function and assembly

Vascular Responses to Shear Stress: The Involvement of Mechanosensors in Endothelial Cells

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