This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 102/8/966    most recent CIRCRESAHA.107.168724v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yin, J. Articles by Kuebler, W. M. Search for Related Content PubMed PubMed Citation Articles by Yin, J. Articles by Kuebler, W. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL NITRIC OXIDE Related Collections Pulmonary circulation and disease Endothelium/vascular type/nitric oxide

(Circulation Research. 2008;102:966.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Negative-Feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-Dependent Regulation of Transient Receptor Potential Vanilloid 4

Jun Yin, Julia Hoffmann, Stephanie M. Kaestle, Nils Neye, Liming Wang, Joerg Baeurle, Wolfgang Liedtke, Songwei Wu, Hermann Kuppe, Axel R. Pries, Wolfgang M. Kuebler

From the Institute of Physiology (J.Y., J.H., S.M.K., N.N., L.W., J.B., A.R.P., W.M.K.), Charité-Universitaetsmedizin Berlin, Germany; Department of Anesthesiology (J.Y., L.W., H.K., W.M.K.), German Heart Institute Berlin, Germany; Departments of Medicine, Neurology, and Neurobiology (W.L.), Duke University, Durham, NC; and Center for Lung Biology (S.W.), University of South Alabama, Mobile.

Correspondence to Prof Dr Wolfgang M. Kuebler, Institute of Physiology, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Arnimallee 22, 14195 Berlin, Germany. E-mail wolfgang.kuebler{at}charite.de

Although the formation of hydrostatic lung edema is generally attributed to imbalanced Starling forces, recent data show that lung endothelial cells respond to increased vascular pressure and may thus regulate vascular permeability and edema formation. In combining real-time optical imaging of the endothelial Ca²⁺ concentration ([Ca²⁺]_i) and NO production with filtration coefficient (K_f) measurements in the isolated perfused lung, we identified a series of endothelial responses that constitute a negative-feedback loop to protect the microvascular barrier. Elevation of lung microvascular pressure was shown to increase endothelial [Ca²⁺]_i via activation of transient receptor potential vanilloid 4 (TRPV4) channels. The endothelial [Ca²⁺]_i transient increased K_f via activation of myosin light-chain kinase and simultaneously stimulated NO synthesis. In TRPV4 deficient mice, pressure-induced increases in endothelial [Ca²⁺]_i, NO synthesis, and lung wet/dry weight ratio were largely blocked. Endothelial NO formation limited the permeability increase by a cGMP-dependent attenuation of the pressure-induced [Ca²⁺]_i response. Inactivation of TRPV4 channels by cGMP was confirmed by whole-cell patch-clamp of pulmonary microvascular endothelial cells and intravital imaging of endothelial [Ca²⁺]_i. Hence, pressure-induced endothelial Ca²⁺ influx via TRPV4 channels increases lung vascular permeability yet concomitantly activates an NO-mediated negative-feedback loop that protects the vascular barrier by a cGMP-dependent attenuation of the endothelial [Ca²⁺]_i response. The identification of this novel regulatory pathway gives rise to new treatment strategies, as demonstrated in vivo in rats with acute myocardial infarction in which inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil reduced hydrostatic lung edema.

Key Words: pulmonary edema • vascular permeability • vascular endothelium • phosphodiesterase type 5 inhibitor • nitric oxide

This article has been cited by other articles:

				S. Wu, M.-Y. Jian, Y.-C. Xu, C. Zhou, A.-B. Al-Mehdi, W. Liedtke, H.-S. Shin, and M. I. Townsley Ca2+ entry via {alpha}1G and TRPV4 channels differentially regulates surface expression of P-selectin and barrier integrity in pulmonary capillary endothelium Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L650 - L657. [Abstract] [Full Text] [PDF]

				R. Kiefmann, M. N. Islam, J. Lindert, K. Parthasarathi, and J. Bhattacharya Paracrine purinergic signaling determines lung endothelial nitric oxide production Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L901 - L910. [Abstract] [Full Text] [PDF]