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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1495.)
© 2006 American Heart Association, Inc.

Vascular Biology

Evidence for a Functional Role of Endothelial Transient Receptor Potential V4 in Shear Stress–Induced Vasodilatation

Ralf Köhler; Willm-Thomas Heyken; Philipp Heinau; Rudolf Schubert; Han Si; Michael Kacik; Christoph Busch; Ivica Grgic; Tanja Maier; Joachim Hoyer

From the Department of Internal Medicine-Nephrology (R.K., W.-T.H., P.H., H.S., M.K., C.B., I.G., T.M., J.H.), Philipps-University, Marburg, Germany; and Institute of Physiology (R.S.), University of Rostock, Germany.

Reprint requests to R. Köhler, Department of Internal Medicine-Nephrology, Philipps-University, Baldingerstrasse, 35033 Marburg, Germany. E-mail rkoehler{at}med.uni-marburg.de

Objective— Ca²⁺-influx through transient receptor potential (TRP) channels was proposed to be important in endothelial function, although the precise role of specific TRP channels is unknown. Here, we investigated the role of the putatively mechanosensitive TRPV4 channel in the mechanisms of endothelium-dependent vasodilatation.

Methods and Results— Expression and function of TRPV4 was investigated in rat carotid artery endothelial cells (RCAECs) by using in situ patch-clamp techniques, single-cell RT-PCR, Ca²⁺ measurements, and pressure myography in carotid artery (CA) and Arteria gracilis. In RCAECs in situ, TRPV4 currents were activated by the selective TRPV4 opener 4-phorbol-12,13-didecanoate (4PDD), arachidonic acid, moderate warmth, and mechanically by hypotonic cell swelling. Single-cell RT-PCR in endothelial cells demonstrated mRNA expression of TRPV4. In FURA-2 Ca²⁺ measurements, 4PDD increased [Ca²⁺]_i by &140 nmol/L above basal levels. In pressure myograph experiments in CAs and A gracilis, 4PDD caused robust endothelium-dependent and strictly endothelium-dependent vasodilatations by &80% (K_D 0.3 µmol/L), which were suppressed by the TRPV4 blocker ruthenium red (RuR). Shear stress–induced vasodilatation was similarly blocked by RuR and also by the phospholipase A₂ inhibitor arachidonyl trifluoromethyl ketone (AACOCF₃). 4PDD produced endothelium-derived hyperpolarizing factor (EDHF)–type responses in A gracilis but not in rat carotid artery. Shear stress did not produce EDHF-type vasodilatation in either vessel type.

Conclusions— Ca²⁺ entry through endothelial TRPV4 channels triggers NO- and EDHF-dependent vasodilatation. Moreover, TRPV4 appears to be mechanistically important in endothelial mechanosensing of shear stress.

Ca²⁺-permeable mechanosensitive channels are believed to be important in endothelial mechanotransduction. The present study provides evidence that the TRPV4 channel, a putatively mechanosensitive member of the TRPV family, mediates wall shear stress–induced vasodilatation in a NO-dependent manner.

Key Words: endothelium-dependent vasodilatation • transient receptor potential • TRPV4 • calcium • shear stress • nitric oxide • 4PDD • rat carotid artery

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