Conference: 2006 International PHA Conference and Scientific Sessions
Release Date: 06.23.2006
Presentation Type: Abstracts
Vanderpool R, Tuchscherer H, Kersten E, Kobs R, Chesler N.
University of Wisconsin – Madison, USA
BACKGROUND. Nitric oxide (NO) is an important vasodilator, and defects in the production of NO have been implicated in the development and progression of pulmonary hypertension (PH). In this study we investigated the role of NO in pulmonary vascular remodelling secondary to pulmonary hypertension using wild type mice and those deficient in endothelial nitric oxide synthase (eNOS).
METHODS. Wild type (+/+) and eNOS-null (-/-) mice were exposed to 10 days of hypobaric hypoxia to stimulate pulmonary vascular remodelling. In both mouse types, isolated vessel and isolated lung experiments were performed. Isolated vessel experiments were used to quantify changes in vascular mechanical properties; specifically, circumferential elastic moduli at low and high pressures and viscoelastic tissue dampening were quantified. Quantitative histology also was performed to determine collagen and elastin content and wall thickness. Isolated lung experiments were used to quantify changes in pulmonary vascular hemodynamics; specifically, pulmonary vascular resistance (PVR), dynamic impedance (PVZ), and metrics of impedance (Z0, ZC, RW) were quantified. All measurements were also obtained in +/+ and -/- mice at 0-day, control conditions.
RESULTS. Vascular mechanics and hemodynamics were significantly affected by hypoxia in both mouse types; also, differences between the +/+ and -/- mice were evident at 0-day condition. Circumferential elastic moduli at low and high pressures as well as viscoelasticity were significantly increased in both mouse types after 10 days of hypoxia. The changes in moduli were correlated with collagen and elastin content. The -/- mice had smaller and more compliant vessels at 0 days but the difference in compliance (i.e., elastic modulus) was normalized by 10 days of hypoxia. Pulmonary vascular resistance, impedance, and metrics of impedance were significantly affected by hypoxia in both mouse types. Pulmonary vascular resistance (PVR) increased, impedance phase decreased, and Z0 and RW increased. ZC tended to as well. The increases in resistance correlated with increased arteriolar muscularization. The -/- mice tended to have higher Z0, higher ZC and lower RW than +/+ mice at the 0-day condition, but these differences were normalized by 10 days of hypoxia.
COMMENTS AND CONCLUSIONS. The consequences of pulmonary artery stiffening in pulmonary hypertension include increased resistance to pulsatile flow, increased wave reflections and increased afterload on the right ventricle. The consequences of increased tissue viscoelasticity include increased energy dissipation, which will also increase right ventricular work requirements. As demonstrated by the isolated lung experiments, conditions which lead to stiffer arteries also lead to increased resistance (PVR and Z0) and wave reflections (RW) although arteriolar muscularization will also affect these hemodynamic parameters. Right ventricular work was not measured in this study. Mice congenitally deficient in eNOS have baseline differences from the wild type mice but, interestingly, these differences disappear after 10 days of hypoxia. Thus, the -/- mice remodel more dramatically than the +/+ mice in response to the same duration of hypoxia. The long term effects of eNOS deficiency on pulmonary vascular remodelling, and consequentially, right heart function in pulmonary hypertension will be the subject of future work. Supported by Whitaker Foundation Grant RG-02-0618.