MOLECULAR SIGNALS IN PULMONARY HYPERTENSION

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The long term goal of this laboratory is to understand the mechanism(s) underlying the development of pulmonary hypertension. The proposal is an extension of our previous investigations of the morphologic, mechanical and pharmacologic properties of isolated arterial vessels in an animal model of pulmonary hypertension induced by hyperoxia. The specific goals of the proposed research are: 1) to understand the molecular bases for alterations in the content of specific structural and contractile proteins which characterize the vascular remodeling that occurs in the experimental model and 2) to directly test the effects of wall tension and oxygen concentration on the regulation of the targeted proteins in isolated arteries. To accomplish these goals we will measure the synthesis rates and mRNA levels for actin isoforms, myosin, collagen types I and III and elastin in pulmonary arteries of normal and hyperoxic rats both in vivo and in vascular segments incubated in vitro. We will use in situ hybridization techniques to identify the cell types in the vessel wall containing these specific mRNAs. Changes in mRNA levels for PDGF-like molecules will be measured and localized to specific cell types in order to assess the involvement of these effectors in the proliferative events that occur. We will relate the results to morphologic, proliferative, and biochemical characteristics of the vessel wall. We will test the hypotheses that increased wall tension and elevated concentrations of oxygen are important factors in the initiation of changes in vascular restructuring. The proposed experiments will provide new information about the molecular events which mediate alterations in vessel structure and function and will provide insights into the direct effects of wall tension and oxygen concentration on parameters relevant to vascular restructuring in pulmonary hypertension.