title: Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1.
abstract: BACKGROUND
  When challenged with extracellular fluid shear stress, vascular endothelial cells are known to release nitric oxide, an important vasodilator. Here, we show that the ability of cultured endothelial cells to sense a low range of fluid shear depends on apical membrane organelles, called cilia, and that cilia are compartments required for proper localization and function of the mechanosensitive polycystin-1 molecule.
  
  
  RESULTS
  Cells with the Pkd1(null/null) or Tg737(orpk/orpk) mutation encoded for polycystin-1 or polaris, respectively, are unable to transmit extracellular shear stress into intracellular calcium signaling and biochemical nitric oxide synthesis. Cytosolic calcium and nitric oxide recordings further show that fluid shear sensing is a cilia-specific mechanism because other mechanical or pharmacological stimulation does not abolish calcium and nitric oxide signaling in polycystin-1 and polaris mutant endothelial cells. Polycystin-1 localized in the basal body of Tg737(orpk/orpk) endothelial cells is insufficient for a fluid shear stress response. Furthermore, the optimal shear stress to which the cells respond best does not alter the apical cilia structure but modifies the responsiveness of cells to higher shear stresses through proteolytic modification of polycystin-1.
  
  
  CONCLUSIONS
  We demonstrate for the first time that polycystin-1 (required for cilia function) and polaris (required for cilia structure) are crucial mechanosensitive molecules in endothelial cells. We propose that a distinctive communication with the extracellular microenvironment depends on the proper localization and function of polycystin-1 in cilia.
authors.affiliation: Department of Pharmacology and Medicine, College of Pharmacy and Medicine, University of Toledo, Toledo, Ohio 43606, USA. Surya.Nauli@UToledo.edu
authors.forename: Surya M
authors.initials: SM
authors.lastname: Nauli
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kawanabe
authors.forename: John J
authors.initials: JJ
authors.lastname: Kaminski
authors.forename: William J
authors.initials: WJ
authors.lastname: Pearce
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D005260:Female; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000096:biosynthesis*; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D033081:Shear Strength; D013314:Stress, Mechanical; D050396:TRPP Cation Channels / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D009569:Nitric Oxide; D050396:TRPP Cation Channels