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Circulation. 2008 Mar 4;117(9):1161-71. doi: 10.1161/CIRCULATIONAHA.107.710111. Epub 2008 Feb 19.

Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1.

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  • 1Department of Pharmacology and Medicine, College of Pharmacy and Medicine, University of Toledo, Toledo, Ohio 43606, USA. Surya.Nauli@UToledo.edu

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.

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.

Comment in

PMID:
18285569
[PubMed - indexed for MEDLINE]
PMCID:
PMC3071982
Free PMC Article

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