Negative-feedback loop attenuates hydrostatic lung edema via a cGMP-dependent regulation of transient receptor potential vanilloid 4.
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 Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](i) via activation of transient receptor potential vanilloid 4 (TRPV4) channels. The endothelial [Ca(2+)](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 [Ca(2+)](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 [Ca(2+)](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 [Ca(2+)](i). Hence, pressure-induced endothelial Ca(2+) 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 [Ca(2+)](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.
Yin
Jun
J
Institute of Physiology, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Arnimallee 22, 14195 Berlin, Germany.
Hoffmann
Julia
J
Kaestle
Stephanie M
SM
Neye
Nils
N
Wang
Liming
L
Baeurle
Joerg
J
Liedtke
Wolfgang
W
Wu
Songwei
S
Kuppe
Hermann
H
Pries
Axel R
AR
Kuebler
Wolfgang M
WM
D000818:Animals; D002118:Calcium / Q000032:analysis; D002199:Capillary Permeability; D006152:Cyclic GMP / Q000502:physiology*; D004594:Electrophysiology; D004730:Endothelium, Vascular; D025461:Feedback, Physiological / Q000502:physiology*; D006874:Hydrostatic Pressure; D066298:In Vitro Techniques; D051379:Mice; D009203:Myocardial Infarction; D009569:Nitric Oxide / Q000032:analysis; D018408:Patch-Clamp Techniques; D011654:Pulmonary Edema / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D050916:TRPV Cation Channels / Q000378:metabolism*
D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D009569:Nitric Oxide; D006152:Cyclic GMP; D002118:Calcium