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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/L650    most recent 00015.2009v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wu, S. Articles by Townsley, M. I. PubMed PubMed Citation Articles by Wu, S. Articles by Townsley, M. I.

Ca²⁺ entry via _1G and TRPV4 channels differentially regulates surface expression of P-selectin and barrier integrity in pulmonary capillary endothelium

¹Center for Lung Biology and ; Department of ²Pharmacology, University of South Alabama College of Medicine, Mobile, Alabama; Department of ³Physiology, University of South Alabama College of Medicine, Mobile, Alabama; Department of ⁴Medicine, University of South Alabama College of Medicine, Mobile, Alabama;; ⁵Departments of Medicine, Neurology, and Neurobiology, Duke University, Durham, North Carolina; and ; ⁶Center for Neural Science, Korea Institute of Science and Technology, Seoul, Korea

Submitted 16 January 2009 ; accepted in final form 12 July 2009

Pulmonary vascular endothelial cells express a variety of ion channels that mediate Ca²⁺ influx in response to diverse environmental stimuli. However, it is not clear whether Ca²⁺ influx from discrete ion channels is functionally coupled to specific outcomes. Thus we conducted a systematic study in mouse lung to address whether the _1G T-type Ca²⁺ channel and the transient receptor potential channel TRPV4 have discrete functional roles in pulmonary capillary endothelium. We used real-time fluorescence imaging for endothelial cytosolic Ca²⁺, immunohistochemistry to probe for surface expression of P-selectin, and the filtration coefficient to specifically measure lung endothelial permeability. We demonstrate that membrane depolarization via exposure of pulmonary vascular endothelium to a high-K⁺ perfusate induces Ca²⁺ entry into alveolar septal endothelial cells and exclusively leads to the surface expression of P-selectin. In contrast, Ca²⁺ entry in septal endothelium evoked by the selective TRPV4 activator 4-phorbol-12,13-didecanoate (4-PDD) specifically increases lung endothelial permeability without effect on P-selectin expression. Pharmacological blockade or knockout of _1G abolishes depolarization-induced Ca²⁺ entry and surface expression of P-selectin but does not prevent 4-PDD-activated Ca²⁺ entry and the resultant increase in permeability. Conversely, blockade or knockout of TRPV4 specifically abolishes 4-PDD-activated Ca²⁺ entry and the increase in permeability, while not impacting depolarization-induced Ca²⁺ entry and surface expression of P-selectin. We conclude that in alveolar septal capillaries Ca²⁺ entry through _1G and TRPV4 channels differentially and specifically regulates the transition of endothelial procoagulant phenotype and barrier integrity, respectively.

T-type calcium channel; transient receptor potential vanilloid 4; vascular permeability