TRP Channels and the Regulation of Vascular Permeability

One of the most widely recognized mechanisms to initiate an inflammatory response is calcium entry into endothelial cells.1–3 Recent investigations have demonstrated that there are multiple mechanisms which determine calcium flux into endothelial cells (including ligand gated calcium channels, store operated calcium channels and mechanosensitive channels), and that these different mechanisms are preferentially distributed between different endothelial cells. The functional consequences of these observations for regulation of vascular tone and remodeling are beginning to be understood4,5 but this is not the case for the regulation of endothelial barrier function in intact organs. In this issue Alvarez et al describe an important example of segmental vascular permeability regulation in lung.6 They demonstrate that activation of the vanilloid subset of the family of calcium channels known as transient receptor potential channels (in this case the TRPV4 channels) preferentially increased the permeability of the endothelial and epithelial layers of the primary gas exchanging septal regions of the lung microvasculature whereas other calcium channels, such as the store operated calcium channels, increased permeability outside the primary gas exchange regions (so called extra-alveolar regions). These are important observations because disruption of the endothelium at the septal barrier is more likely to cause alveolar flooding and impair gas exchange than disruption in extraalveolar vessels. So far at least 28 mammalian TRP isoforms have been discovered. TRP channels have been subdivided into 3 main classes, TRPC (canonical), TRPM (melastatin), and TRPV (vanilloid) although more recently other classes have also been proposed (TRPP [polycystin], TRPML [mucolipin], and TRPA [ankyrin]).4,7 A general feature of the channels is that they pass only very small currents (calcium ion flux) and act as passive conductance pathways for calcium entry, ie, they are not voltage gated. Thus the calcium flux depends on the local density of channel expression and the electrochemical driving force driving calcium into the cell. In particular hyperpolarization of the endothelial cell membrane potentiates calcium entry by increasing the electrical driving force for positively charged ions such as calcium. For example, when TRP channels are activated close to calcium regulated potassium channels, they may also hyperpolarize the membrane and amplify calcium influx through all open calcium channels. As described in recent reviews, TRP channels have many functions in the vasculature4 including the regulation of vascular tone (TRPC4, TRPV1, TRPV4), angiogenesis (TRPM6 and TRPM7), vascular remodeling (TRPC4), oxidative stress-induced responses (TRPC3, TRPC4, TRPM2) and mechanosensing (TRPV4). TRP channels have also been implicated in the regulation of vascular permeability including TRPC1, TRPC4, TRPC6, and TRPV1.4 With relatively few specific antagonists for the TRP channels available at this time, it can be difficult to identify which TRP channel is involved in a given signaling event. Alvarez et al have used several strategies to distinguish the TRP channels in their lung preparation. As discussed below there are limitations to the confidence that can be placed in any one of these strategies, but a strength of the present article is that it focuses attention of several converging themes that are important for further investigations of calcium dependent regulation of fluid accumulation in the lung. The strategies used by Alvarez et al include immunohistochemical localization of TRPV4 expression, light and electron microscopy of localized breaks in the endothelial barrier, selective activation of the channels, with particular attention of the role the arachidonic acid metabolites (EETs, epoxyeicosatrienoic acids), use of putative selective blocking of calcium entry, and the use of TRPV4 / mice. The importance of using a multiple approach is well illustrated by the following example. The authors measure changes in the lung filtration coefficient to report modulation of lung vascular permeability. The filtration coefficient is determined from the rate of fluid accumulation (lung weight) after a step increase in microvessel pressure. They demonstrate that the increase in filtration coefficient after exposure to a putative activator of TRP4 channels is attenuated in TRPV4 / mice. These results support a role for TRPV4 in the regulation of permeability only if the known role of TRPV4 as a modulator of vascular tone is not a dominant mechanism. For example, at least part of the increase in lung weight after activating TRPV4 channels could involve recruitment of more blood vessels resulting in an increase in vascular volume and surface area available for fluid filtration. As appropriate, the authors attempt to distinguish such changes in vascular volume from true changes in hydraulic conductivity (a measure of vascular permeability) by only measuring fluid accumulation after a period when changes in vascular tone are assumed to have ceased. Nevertheless the loss of TRPV4 dependent mechanisms of vascular recruitment in knockout mice could be misinterpreted as a reduced permeability. In this regard the The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis. Correspondence to Fitz-Roy E. Curry, University of California, Department of Human Physiology, Davis School of Medicine, One Shields Avenue, Davis, CA 95616. E-mail [email protected] (Circ Res. 2006;99:915–917.) © 2006 American Heart Association, Inc.