PS 04-26 PHARMACOLOGICAL ACTIVATION OF TRPV4 BY GSK1016790A ATTENUATES ARTERIOGENESIS TRIGGERED BY INCREASED SHEAR STRESS

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Abstract

Objective:

Arteriogenesis may aid the efforts in lowering vascular resistance and improving organ blood flow if it can be controlled. A previous claim that pharmacological activation of TRPV4 channels using 4α-Phorbol 12,13-didecanoate (4αPDD), a non-selective agonist, enhanced arteriogenesis in the posterior cerebral circulation (Schierling et al., 2011) was examined using a highly selective TRPV4 agonist - GSK1016790A.

Design and Method:

Increased shear stress in the cerebral circulation was induced by bilateral occlusion of the common carotid arteries (BCL). Sprague-Dawley rats were subjected to either: sham, BCL, BCL+vehicle, BCL+4αPDD, BCL+GSK1016790A. The vehicle and drugs were delivered by osmotic minipump (7 days) into the cerebral circulation via a carotid artery. Brain casts using ink/gelatine contrast medium were examined.

Results:

BCL increased basilar artery diameter relative to sham (348 ± 14 vs 224 ± 23 μm, respectively, p < 0.001). The vehicle control did not differ from the BCL (BCL+vehicle 360.2 ± 42.42 μm). There was a difference between BCL/vehicle and sham control (360 ± 42 vs 224 ± 23 μm respectively, p < 0.01). The two TRPV4 agonists had an opposite effect on the basilar artery diameter. BCL+4αPDD group had basilar arteries that remodelled to the same extent as the BCL only group (400 ± 51 vs 348 ± 14 μm, respectively, NS) whereas infusion of GSK1016790A attenuated the remodelling induced by BCL (294 ± 22 vs 348 ± 14 μm respectively, p < 0.05). A 7 day recovery from GSK1016790A increased basilar artery diameter (407 ± 43 μm, p < 0.05). Similar findings were apparent in the vertebral arteries also.

Conclusions:

Activation of TRPV4 channels using a selective agonist attenuates posterior cerebral circulation arteriogenesis triggered by increased shear stress model. Thus, we do not support the contention that TRPV4 channel activity would be a therapeutic target to increase organ blood flow.

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