Medial and/or intimal thickening of the pulmonary arterial wall, secondary to smooth muscle cell (SMC) hyperplasia and excessive production of extracellular matrix proteins, is commonly observed in neonatal, infant and adult forms of pulmonary hypertension. The vascular remodeling is the result of dramatic changes in the proliferative and synthetic capabilities of arterial SMC and is known to directly contribute to the abnormalities in vascular tone and resistance that characterize chronic forms of pulmonary hypertension. However, studies in the systematic circulation as well as their recent studies in the pulmonary circulation have suggested that the vascular media is not homogenous but rather is composed of multiple phenotypically distinct sub-populations. Therefore, an understanding of the vascular remodeling associated with pulmonary hypertension requires detailed study of both the cellular composition of the pulmonary arterial media as well as the differential responses exhibited by distinct SMC sub-populations to pathophysiological stimuli. They thus propose to test the hypothesis that phenotypically distinct SMC populations exist in the pulmonary circulation and exhibit unique cytodifferentiation, proliferative and matrix protein synthetic responses to stimuli causing pulmonary hypertension and thus contribute in unique and selective ways to the remodeling process. Utilizing immunohistochemical and in situ hybridization techniques they will examine in vivo changes in differentiation and some important cellular functions including proliferation and elastin synthesis which occur in the various SMC sub-populations during normal development and in response to hypoxia-induced pulmonary hypertension. Further, they will isolate in vitro, phenotypically distinct SMC sub-populations from the mature and developing vascular media and then study some of the mechanisms which contribute to the unique growth and tropoelastin producing differences in these cell populations to better understand the roles of phenotypically distinct SMC populations in the vascular media. They will also study SMC from the hypertensive vessel wall to determine mechanisms contributing to their altered growth properties. They believe this approach will allow identification of the specific SMC populations whose abnormal growth and synthetic behavior contribute the most to vascular remodeling and the genes responsible for this cell behavior. These studies will provide information necessary for developing experimental and therapeutic strategies aimed at inhibiting the vascular remodeling in the neonatal period.
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