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Chronic Hypoxia Augments Endothelin‐1‐Dependent Pulmonary Vascular Smooth Muscle Ca 2+ Sensitivity
Author(s) -
Resta Thomas C.,
Snow Jessica B.,
Broughton Brad R.S.,
Walker Benjimen R.
Publication year - 2006
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.20.4.a402-c
Subject(s) - hypoxic pulmonary vasoconstriction , vasoconstriction , rho associated protein kinase , rhoa , pulmonary hypertension , endothelin 1 , medicine , endocrinology , endothelin receptor , vascular smooth muscle , pulmonary artery , hypoxia (environmental) , chemistry , receptor , signal transduction , smooth muscle , biochemistry , oxygen , organic chemistry
Recent evidence from our laboratory and others indicates that chronic hypoxia (CH) augments agonist‐induced RhoA and Rho kinase (ROK) activity, increases ROK expression, and enhances ROK‐dependent myofilament Ca 2+ sensitivity in pulmonary vascular smooth muscle (VSM). The RhoA/ROK signaling pathway has been further implicated in mediating pulmonary VSM contraction to endothelin‐1 (ET‐1), an endothelium‐derived vasoconstrictor peptide that contributes to the development of CH‐induced pulmonary hypertension. We therefore hypothesized that CH augments ET‐1‐mediated Ca 2+ sensitization in pulmonary VSM. To test this hypothesis, we assessed vasoconstrictor responses to ET‐1 (10 −10 –10 −7 M) in endothelium‐denuded, pressurized pulmonary arteries (151 ± 12 μm inner diameter) from control and CH (4 wk at P B = 380 mmHg) rats. Arteries were permeabilized to Ca 2+ with ionomycin (3 μM), superfused with a physiological saline solution containing 300 nM Ca 2+ , and loaded with fura‐2 AM to verify that VSM intracellular free Ca 2+ concentration was maintained constant during ET‐1‐induced vasoconstriction. In agreement with our hypothesis, vasoconstriction to ET‐1 (10 −9 –10 −7 M) was markedly enhanced in CH vs. control arteries. We conclude that CH increases ET‐1‐induced myofilament Ca 2+ sensitivity in pulmonary VSM. (Supported by NIH grants HL‐07736, HL‐77876, HL‐58124 and HL‐63207)