Lung endothelial TRPV channels are downregulated in heart failure

Abstract

Lung vascular endothelial cells respond to hydrostatic stress by Ca2+-dependent NO formation, but this response is absent in congestive heart failure (CHF). Here, we investigated whether downregulation of mechanosensitive TRPV Ca2+-channels may account for endothelial dysfunction in CHF. CHF was induced in rats by supracoronary aortic banding 8 weeks prior to investigations. In isolated perfused lungs, endothelial Ca2+ concentration ([Ca2+]i) and NO were quantified by in situ fluorescence imaging of fura-2 and DAF-FM. Western blot analyses were performed with protein from freshly isolated pulmonary endothelial cells or homogenized lungs. Data are means ± SEM, ∗ p<0.05 vs. baseline, # p<0.05 vs. control. Elevation of left atrial pressure (PLA) from 5 to 15 cmH2O increased [Ca2+]i from 102±3 nM to 172±8 nM∗ in control but not CHF lungs (86±2 nM vs. 91±4 nM). Similarly, NO production was increased to 239±18%∗ (of baseline) compared with 98±2%# in CHF lungs. In control lungs, inhibition of TRPV channels by ruthenium red (10μM) attenuated the endothelial [Ca2+]i response to 108±4 nM#. Western blot analyses showed a reduced expression of TRPV2 (66%±3) and TRPV4 (75%±5#) in CHF as compared to control lungs. Downregulation of mechanosensitive TRPV channels, which play a critical role in lung endothelial responses to hydrostatic stress, may contribute to endothelial dysfunction in CHF. Sponsored by EU-IP “Pulmotension”