This project aims to characterize vascular smooth muscle cell (SMC) diversity in the pulmonary circulation as a function of development and injury. Using in situ hybridization to investigate matrix protein synthesis by cells in normal and diseased vessels, we discovered a cellular complexity that required a reconsideration of the widely held concept that the vessel wall contains a homogenous population of SMCs. The phenotypic diversity we observed dictates that to understand the cellular mechanisms associated with vascular remodeling in pulmonary hypertension, a more detailed characterization of the diverse cell populations is required. Thus, one of our objectives in this renewal is to explore the possibility that different smooth muscle cell types make unique contributions to the disease processes associated with pulmonary hypertension. In this context, we propose to investigate whether elastin gene expression provides a marker to identify the different smooth muscle phenotypes. We will also utilize differential cloning to identify genes that are unique to the hypertensive state and determine expression patterns of these genes in normal and injured pulmonary arteries. To properly interpret phenotypic modulation in response to injury, however, we must first understand the normal developmental changes a cell is programmed to undergo. Therefore, another objective will be to characterize cell phenotypes in pulmonary arteries and veins in development, focusing on the elastin phenotype. Elastin is an important vascular protein in its own right but its organization into an elastic fiber requires several other proteins that make up the microfibrils. It is now clear that the elastin phenotype is much more complex than simply elastin production. An important objective of this proposal is to utilize newly developed reagents for microfibrillar proteins to develop a more complete characterization of the elastin phenotype in vascular cells. Understanding how these components of the elastic fiber are regulated in the developing pulmonary vessel is critical to understanding their expression in vascular repair.
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