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(Circulation. 2008;117:1161-1171.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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

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

From the Department of Pharmacology and Medicine, College of Pharmacy and Medicine, University of Toledo, Toledo, Ohio (S.M.N.); Department of Neurosurgery, Takatsuki Red Cross Hospital, Takatsuki, Osaka,, Japan (Y.K.); Department of Biology, Boston University, Boston, Mass (J.J.K.); Department of Pharmacology, Loma Linda Medical School, Loma Linda, Calif (W.J.P.); Vascular Biology Program, Children’s Hospital, Harvard Medical School, Boston, Mass (D.E.I.); and Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (J.Z.).

Correspondence to Surya M. Nauli, PhD, University of Toledo, Department of Pharmacology, MS 607, Wolfe Hall Bldg, Room 2243, 2801 W Bancroft St, Toledo, OH 43606. E-mail Surya.Nauli{at}UToledo.edu

Received April 18, 2007; accepted November 15, 2008.

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.

Methods and 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.

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