title: Endothelial hyperpermeability in severe pulmonary arterial hypertension: role of store-operated calcium entry.
abstract: Here, we tested the hypothesis that animals with severe pulmonary arterial hypertension (PAH) display increased sensitivity to vascular permeability induced by activation of store-operated calcium entry. To test this hypothesis, wild-type and transient receptor potential channel 4 (TRPC4) knockout Fischer 344 rats were given a single injection of Semaxanib (SU5416; 20 mg/kg) followed by 3 wk of exposure to hypoxia (10% oxygen) and a return to normoxia (21% oxygen) for an additional 2-3 wk. This Semaxanib/hypoxia/normoxia (i.e., SU5416/hypoxia/normoxia) treatment caused PAH, as evidenced by development of right ventricular hypertrophy, pulmonary artery medial hypertrophy, and occlusive lesions within precapillary arterioles. Pulmonary artery pressure was increased fivefold in Semaxanib/hypoxia/normoxia-treated animals compared with untreated, Semaxanib-treated, and hypoxia-treated controls, determined by isolated perfused lung studies. Thapsigargin induced a dose-dependent increase in permeability that was dependent on TRPC4 in the normotensive perfused lung. This increase in permeability was accentuated in PAH lungs but not in Semaxanib- or hypoxia-treated lungs. Fluid accumulated in large perivascular cuffs, and although alveolar fluid accumulation was not seen in histological sections, Evans blue dye conjugated to albumin was present in bronchoalveolar lavage fluid of hypertensive but not normotensive lungs. Thus PAH is accompanied by a TRPC4-dependent increase in the sensitivity to edemagenic agents that activate store-operated calcium entry.
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; and.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Department of Internal Medicine, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; and.
authors.forename: Mary I
authors.initials: MI
authors.lastname: Townsley
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; and.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Alexeyev
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Department of Internal Medicine, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; and tstevens@southalabama.edu.
authors.forename: Troy
authors.initials: T
authors.lastname: Stevens
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D020013:Calcium Signaling; D015687:Cell Hypoxia; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010539:Permeability / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D011916:Rats, Inbred F344; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D007211:Indoles; D011758:Pyrroles; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D019284:Thapsigargin; C116890:Semaxinib
keywords: Semaxanib; Sugen 5416; TRPC4; calcium channels; canonical transient receptor potential 4; edema; filtration coefficient