ALTERATIONS OF GROWTH-FACTOR TRANSCRIPTS IN RAT LUNGS DURING DEVELOPMENT OF MONOCROTALINE-INDUCED PULMONARY-HYPERTENSION

Although pathologic and hemodynamic changes in monocrotaline (MCT)-ind uced pulmonary hypertension have been studied extensively. relatively little is known about the inter- and intracellular signaling mechanism s underlying such alterations. As a first step to delineating signalin g mechanisms governing adverse structural alterations in the hypertens ive lungs, we examined changes in the steady-state levels of mRNAs enc oding several growth factors including transforming growth factors (TG F), platelet-derived growth factors (PDGF), vascular endothelial cell growth factor (VEGF) and endothelin (ET) as a function of time in MCT- induced pulmonary hypertension in rats. These studies demonstrated a v ery diverse pattern of growth factor gene expression in response to MC T administration. In general, alterations in the steady-state levels o f mRNAs encoding the growth factors preceded the onset of MCT-induced pulmonary hypertension. TGF-beta1, -beta2 and -beta3 transcripts were seen to be elevated, whereas that of TGF-alpha and PDGF-A remained unc hanged. Transcripts for PDGF-B and ET were increased in the early stag es but declined to less than controls in the latter stages of MCT-indu ced hypertension. In contrast, levels of VEGF mRNA decreased to less t han controls as the disease progressed. Viewed collectively, the diver se pattern of expression suggests that alterations in the levels of th e growth factor transcripts may have a significant role in the develop ment of pulmonary hypertensive disease and may be relevant to the path ological and structural changes in MCT-induced pulmonary hypertension.