期刊
CIRCULATION RESEARCH
卷 102, 期 8, 页码 966-974出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.168724
关键词
pulmonary edema; vascular permeability; vascular endothelium; phosphodiesterase type 5 inhibitor; nitric oxide
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 Kf 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.
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