Actin Polymerization Contributes To Enhanced Pulmonary Arterial Vasoconstrictor Reactivity Following Chronic Hypoxia

Chronic hypoxia (CH) induces basal pulmonary arterial tone and augments vasoconstrictor reactivity to endothelin‐1 (ET‐1) through Rho kinase‐dependent Ca2+ sensitization. Considering that dynamic actin cytoskeletal reorganization is integral to tension generation in smooth muscle, and that Rho kinase is important in mediating actin polymerization, we hypothesized that actin polymerization is required for both basal pulmonary arterial tone and enhanced ET‐1‐dependent vasoconstriction following CH. To test this hypothesis, we assessed effects of the actin polymerization inhibitors, cytochalasin B (10‐5 M) and latrunculin A (10‐5 M), on the development of tone in response to increasing intraluminal pressure steps (5‐45 mmHg) in isolated, endothelium‐disrupted pulmonary arteries (~150 μm diameter) from control and CH (4 wk at 0.5 atm) rats. Further experiments examined effects of cytochalasin B on constrictor responses to ET‐1 (10‐10 ‐ 10‐7 M) under Ca2+‐clamp conditions in arteries from each group. Consistent with our hypothesis, inhibitors of actin polymerization prevented basal tone (p<0.05 vs. vehicle) and attenuated ET‐1‐mediated constriction (p<0.05 vs. vehicle) in arteries from CH rats, while having no effect on control arteries. We conclude that actin polymerization is necessary for generation of basal pulmonary arterial tone and enhanced vasoconstrictor reactivity to ET‐1 following CH. Grant Funding Source : Supported by NIH R01 HL88192 and NIH T32 HL07736