Remodeling of lung vessels in lung diseases contributes to mismatch of perfusion and ventilation, inefficient gas exchange, systemic hypoxemia, pulmonary hypertension, and cor pulmonale. Remodeling is conventionally defined by changes in connective tissue and smooth muscle composition of the vessel wall. Hypoxia promotes remodeling both as a primary chemical stimulus and by generating secondary mechanical stimuli. The motivating hypothesis is that changes in pulmonary vascular lumenal architecture, wall mechanics, and pressure-flow relationship that occur with hypoxia in the rat can be dissociated from vascular remodeling defined by the conventional histological criteria. Thus, the definition needs to be extended to include the changes in vascular architecture and vessel mechanics that are more immediately related to vascular function and not directly predictable from histology alone. This hypothesis follows from the observation that the histologically defined remodeling can be dissociated from the hypertension by treatments such as inhibition of angiotensin converting enzyme (ACE). The rationale for addressing this hypothesis is that knowledge of remodeling stimuli and the ability to separate contributory from compensatory remodeling events are required to evaluate the significance of information obtained from cellular and molecular studies directed at a particular remodeling stimulus-response pathway.
Specific Aims are to: 1) Determine the effects of acute hypoxic vasoconstriction on geometric and mechanical properties of pulmonary arteries, veins, and capillary bed, and how changes in these properties affect the longitudinal and parallel distributions of stresses and strains on and within the vessel walls; 2) Determine how the properties measured under Aim 1 are affected by vascular remodeling induced by chronic hypoxia with or without cotreatment with an ACE inhibitor or antioxidant, and 3) Continue development of a mathematical model of the pulmonary circulation to evaluate the functional implications of the observations from Aims 1 and 2. The primary measurement tool will be x-ray microangiography in dynamic planar and static three dimensional imaging modes. Continued development of the angiographic methods and hemodynamic model, having broader applications to related and other problems, is also expected to be a significant scientific contribution of the proposed studies.
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