Negative-Feedback Loop Attenuates The Hydrostatic Lung Edema

Heart failure is becoming an important cardiovascular disease. And hydrostatic pulmonary edema is a severe complication of heart failure. Although the formation of hydrostatic pulmonary edema is generally attributed to imbalanced Starling forces, recent data show that lung endothelial cells can respond to increased vascular pressure and may thus regulate vascular permeability and edema formation. Transient receptor potential vanilloid4 (TRPV4) and phosphodiesterase5 (PDE5) expression in lung vascular endothelial cells was confirmed by Western blotting and immunohistochemistry. 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 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 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 PDE5 inhibitor sildenafil reduced hydrostatic lung edema.