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Role of Caveolin 1 in Membrane Depolarization‐Inducd Ca 2+ ‐Sesnsitization in Pulmonary Vascular Smooth Muscle Following Chronic Hypoxia
Author(s) -
Norton Charles Elbert,
Walker Benjimen R.,
Resta Thomas C.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1034.5
Subject(s) - depolarization , vascular smooth muscle , sensitization , rhoa , chemistry , pulmonary hypertension , endocrinology , medicine , hypoxia (environmental) , biophysics , vasodilation , superoxide , membrane potential , biology , signal transduction , biochemistry , neuroscience , oxygen , smooth muscle , organic chemistry , enzyme
We have previously shown that chronic hypoxia (CH) augments depolarization induced Ca 2+ ‐sensitization in pulmonary vascular smooth muscle (VSM) through superoxide anion (O 2 − )‐dependent activation of RhoA. Caveolin‐1 (cav‐1) is a membrane‐associated scaffolding protein that also functions to regulate intracellular trafficking and activity of various signaling proteins. Based on evidence that reduced pulmonary vascular cav‐1 expression contributes to monocrotaline induced pulmonary hypertension, we hypothesized that enhanced depolarization‐induced myofilament Ca 2+ sensitization following CH results from the loss of cav‐1 mediated inhibition of this signaling pathway. To test our hypothesis, we examined vasoconstrictor responses to depolarizing concentrations of KCl (30–120 mM) following administration of either a peptide containing the scaffolding domain of cav‐1 (AP‐Cav; 10 μM) or a scrambled control peptide in pressurized small pulmonary arteries from control and CH (4 wk at 0.5 atm) rats. Arteries were endothelium‐disrupted, Ca 2+ permeabilized, and loaded with fura‐2 AM to confirm that VSM [Ca 2+ ] i remained constant. Consistent with our hypothesis, AP‐Cav selectively inhibited KCl‐dependent constriction in CH arteries and normalized reactivity between groups. We conclude that cav‐1 dysfunction facilitates depolarization‐induced pulmonary VSM Ca 2+ ‐sensitization following CH.