Lung endothelial dysfunction in heart failure: Role of impaired Ca2+ signaling and cytoskeletal reorganization

Abstract

Congestive heart failure (CHF) causes lung endothelial (EC) dysfunction, which in turn aggravates lung vascular remodeling and right ventricular failure. Here, we elucidated the mechanisms underlying lung EC dysfunction in a rat model of CHF induced by supracoronary aortic banding. Lung EC dysfunction was evident in CHF as impaired EC‐dependent vasodilation and NO synthesis in response to mechanical stress, acetylcholine or histamine, although expression of endothelial NO synthase was unmitigated. Reconstitution of cytosolic Ca2+ ([Ca2+]i) signaling by Ca2+ ionophore restored NO production. Impaired lung EC [Ca2+]i homeostasis and signaling in CHF in response to mechanical stress, histamine, acetylcholine or thapsigargin was confirmed by real‐time fluorescence imaging, yet was not attributable to downregulation of EC Ca2+ influx channels. Rather, we identified a massive remodeling of the endothelial cytoskeleton by increased β‐actin expression and F‐actin formation, which contributed critically to endothelial dysfunction in CHF, since cytoskeletal disruption by cytochalasin reconstituted endothelial [Ca2+]i signaling and NO production. Our findings show that lung EC dysfunction in CHF results from impaired EC [Ca2+]i signaling, and identify the endothelial cytoskeleton as critical regulator of EC [Ca2+]i homeostasis.Sponsored by EU IP Pulmotension and Kaiserin‐Friedrich Foundation Berlin.