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J. Biol. Chem., Vol. 281, Issue 48, 36492-36500, December 1, 2006

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Flow-activated Chloride Channels in Vascular Endothelium

SHEAR STRESS SENSITIVITY, DESENSITIZATION DYNAMICS, AND PHYSIOLOGICAL IMPLICATIONS^*

Mamta Gautam, Yue Shen, Twanda L. Thirkill, Gordon C. Douglas, and Abdul I. Barakat¹

From the Department of Mechanical and Aeronautical Engineering and the Department of Cell Biology and Human Anatomy, University of California, Davis, California 95616

Although activation of outward rectifying Cl^– channels is one of the fastest responses of endothelial cells (ECs) to shear stress, little is known about these channels. In this study, we used whole-cell patch clamp recordings to characterize the flow-activated Cl^– current in bovine aortic ECs (BAECs). Application of shear stress induced rapid development of a Cl^– current that was effectively blocked by the Cl^– channel antagonist 5-nitro-2-(3-phenopropylamino)benzoic acid (100 µM). The current initiated at a shear stress as low as 0.3 dyne/cm², attained its peak within minutes of flow onset, and saturated above 3.5 dynes/cm^{2 (}2.5–3.5-fold increase over pre-flow levels). The Cl^– current desensitized slowly in response to sustained flow, and step increases in shear stress elicited increased current only if the shear stress levels were below the 3.5 dynes/cm² saturation level. Oscillatory flow with a physiological oscillation frequency of 1 Hz, as occurs in disturbed flow zones prone to atherosclerosis, failed to elicit the Cl^– current, whereas lower oscillation frequencies led to partial recovery of the current. Nonreversing pulsatile flow, generally considered protective of atherosclerosis, was as effective in eliciting the current as steady flow. Measurements using fluids of different viscosities indicated that the Cl^– current is responsive to shear stress rather than shear rate. Blocking the flow-activated Cl^– current abolished flow-induced Akt phosphorylation in BAECs, whereas blocking flow-sensitive K⁺ currents had no effect, suggesting that flow-activated Cl^– channels play an important role in regulating EC flow signaling.

Received for publication, June 19, 2006 , and in revised form, September 6, 2006.

^* This work was supported in part by an Atorvastatin Research Award from Pfizer/Parke-Davis and by Philip Morris (to A. I. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Mechanical and Aeronautical Engineering, University of California, One Shields Ave., Davis, CA 95616. Tel.: 530-754-9295; Fax: 530-752-4158; E-mail: abarakat{at}ucdavis.edu.

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