title: Lung endothelial dysfunction in congestive heart failure: role of impaired Ca2+ signaling and cytoskeletal reorganization.
abstract: BACKGROUND
  Congestive heart failure (CHF) frequently results in remodeling and increased tone of pulmonary resistance vessels. This adaptive response, which aggravates pulmonary hypertension and thus, promotes right ventricular failure, has been attributed to lung endothelial dysfunction.
  
  
  OBJECTIVE
  We applied real-time fluorescence imaging to identify endothelial dysfunction and underlying molecular mechanisms in an experimental model of CHF induced by supracoronary aortic banding in rats.
  
  
  RESULTS
  Endothelial dysfunction was evident in lungs of CHF rats as impaired endothelium-dependent vasodilation and lack of endothelial NO synthesis in response to mechanical stress, acetylcholine, or histamine. This effect was not attributable to downregulation of endothelial NO synthase. Imaging of the cytosolic Ca(2+) concentration ([Ca(2+)](i)) revealed a singular impairment of endothelial [Ca(2+)](i) homeostasis and signaling characterized by a lack of [Ca(2+)](i) oscillations and deficient or attenuated [Ca(2+)](i) responses to mechanical stress, histamine, acetylcholine, or thapsigargin. Reconstitution of a [Ca(2+)](i) signal by ionophore treatment restored endothelial NO production, but lack of endothelial responsiveness was not primarily attributable to downregulation of Ca(2+) influx channels in CHF. Rather, we identified a massive remodeling of the endothelial cytoskeleton in the form of an increased expression of beta-actin and F-actin formation which contributed critically to endothelial dysfunction in CHF because cytoskeletal disruption by cytochalasin D largely reconstituted endothelial [Ca(2+)](i) signaling and NO production.
  
  
  CONCLUSIONS
  Our findings characterize a unique scenario of endothelial dysfunction in CHF that is caused by a singular impairment of [Ca(2+)](i) signaling, and identify cytoskeletal reorganization as a major regulator of endothelial signaling and function.
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kerem
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Kaestle
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Axel M
authors.initials: AM
authors.lastname: Schoene
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.forename: Hermann
authors.initials: H
authors.lastname: Kuppe
authors.forename: Mathias M
authors.initials: MM
authors.lastname: Borst
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D020013:Calcium Signaling / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006632:Histamine / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007476:Ionophores / Q000494:pharmacology; D008168:Lung / Q000098:blood supply*; D008297:Male; D008856:Microscopy, Fluorescence; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013997:Time Factors; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000199:Actins; D018680:Cholinergic Antagonists; D007476:Ionophores; D020030:Nitric Oxide Donors; D050051:Transient Receptor Potential Channels; D014665:Vasodilator Agents; D015638:Cytochalasin D; D009569:Nitric Oxide; D006632:Histamine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine