We propose to identify cell markers of medial hypertrophy/hyperplasia characteristic of pulmonary hypertension in rats. Studies are planned to investigate changes which may parallel alterations in membrane properties of smooth muscle cells located in large (conducting) and small (muscular) arteries in the pulmonary bed of normal and hypertensive rats. Additional studies are proposed to examine similar correlates of pulmonary hypertension in normally innervated and adrenergically denervated guinea pigs. Analyses will primarily involve gel electrophoresis (single-dimensional and two-dimensional) and immunocytochemical localization of putative markers in cells from loci along the pulmonary artery in which morphological and physiological changes have been identified. The media of small pulmonary arteries in species such as man and rat, in response to chronic hypoxia, undergoes a remodelling which contributes to pulmonary vascular resistance. In the main pulmonary arteries, there is medial thickening and increased secretion of collagen and elastin. Such observations point to a need for investigations of macromolecules, such as myosin, desmin and vimentin, known to be involved in cytoskeletal structures. Elastin, secreted by smooth muscle cells, will also be investigated. In addition, it is crucial to determine whether there are other definable constituent differences characteristic of smooth muscle heterogeneity which respond to physiologic stimuli associated with pulmonary hypertension. This project will be carried out in conjunction with an ongoing study of membrane properties, contractility and innervation of smooth muscle fibers in the main and small pulmonary arteries of normal and hypertensive rats and guinea pigs. The long-term goal of these studies is to understand control mechanisms for contractility, stretch resistance and relaxation in vascular smooth muscle as mediated by neurotransmitters, pharmacological agents and trophic factors. The systematic correlation of these two approaches will provide insights into the involvement of smooth muscle in clinical states of pulmonary and systemic hypertension and, in particular, into mechanisms underlying changes of reactivity in this model of hypertension.
| Twarog, B M; Takuno, H; Petrou, S et al. (1988) Pathogenesis of pulmonary hypertension in the rat model. Chest 93:100S-101S |
