Arterial Response to Shear Stress Critically Depends on Endothelial TRPV4 Expression
Open Access
- 4 September 2007
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 2 (9), e827
- https://doi.org/10.1371/journal.pone.0000827
Abstract
Background. In blood vessels, the endothelium is a crucial signal transduction interface in control of vascular tone and blood pressure to ensure energy and oxygen supply according to the organs' needs. In response to vasoactive factors and to shear stress elicited by blood flow, the endothelium secretes vasodilating or vasocontracting autacoids, which adjust the contractile state of the smooth muscle. In endothelial sensing of shear stress, the osmo- and mechanosensitive Ca2+-permeable TRPV4 channel has been proposed to be candidate mechanosensor. Using TRPV4(-/-) mice, we now investigated whether the absence of endothelial TRPV4 alters shear-stress-induced arterial vasodilation. Methodology/Principal Findings. In TRPV4(-/-) mice, loss of the TRPV4 protein was confirmed by Western blot, immunohistochemistry and by in situ-patch-clamp techniques in carotid artery endothelial cells (CAEC). Endothelium-dependent vasodilation was determined by pressure myography in carotid arteries (CA) from TRPV4(-/-) mice and wild-type littermates (WT). In WT CAEC, TRPV4 currents could be elicited by TRPV4 activators 4 alpha-phorbol-12,13-didecanoate (4 alpha PDD), arachidonic acid ( AA), and by hypotonic cell swelling (HTS). In striking contrast, in TRPV4(-/-) mice, 4 alpha PDD did not produce currents and currents elicited by AA and HTS were significantly reduced. 4 alpha PDD caused a robust and endothelium-dependent vasodilation in WT mice, again conspicuously absent in TRPV4(-/-) mice. Shear stress-induced vasodilation could readily be evoked in WT, but was completely eliminated in TRPV4(-/-) mice. In addition, flow/reperfusion-induced vasodilation was significantly reduced in TRPV4(-/-) vs. WT mice. Vasodilation in response to acetylcholine, vasoconstriction in response to phenylephrine, and passive mechanical compliance did not differ between genotypes, greatly underscoring the specificity of the above trpv4-dependent phenotype for physiologically relevant shear stress. Conclusions/Significance. Genetically encoded loss-of-function of trpv4 results in a loss of shear stress-induced vasodilation, a response pattern critically dependent on endothelial TRPV4 expression. Thus, Ca2+-influx through endothelial TRPV4 channels is a molecular mechanism contributing significantly to endothelial mechanotransduction.Keywords
This publication has 53 references indexed in Scilit:
- Altered acetylcholine, bradykinin and cutaneous pressure‐induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial linkEMBO Reports, 2007
- TRPV4 as a flow sensor in flow-dependent K+ secretion from the cortical collecting ductAmerican Journal of Physiology-Renal Physiology, 2007
- Protease‐activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in miceThe Journal of Physiology, 2007
- Transient Receptor Potential Vanilloid 4–Mediated Disruption of the Alveolar Septal BarrierCirculation Research, 2006
- TRPV4‐mediated regulation of epithelial permeabilityThe FASEB Journal, 2006
- A Transient Receptor Potential Vanilloid 4-Dependent Mechanism of Hyperalgesia Is Engaged by Concerted Action of Inflammatory MediatorsJournal of Neuroscience, 2006
- Functional TRPM7 Channels Accumulate at the Plasma Membrane in Response to Fluid FlowCirculation Research, 2006
- Endotheliale Ionenkanäle - neue Targets der Hypertonietherapie?Deutsche Medizinische Wochenschrift (1946), 2005
- International Union of Pharmacology. XLIII. Compendium of Voltage-Gated Ion Channels: Transient Receptor Potential ChannelsPharmacological Reviews, 2003
- The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholineNature, 1980