Morphologically and immunohistochemically distinct SMC phenotypes exist within the systemic arterial media of mammals, but it is not known how they develop, what makes them unique, how they respond to physiologic stimuli and whether they influence other cells. The mature and developing pulmonary circulation also has multiple unique SMC subpopulations based on our findings of differential expression of muscle-specific markers, and diverse profiles of tropoelastin mRNA expression. Our analysis, using muscle-specific cytoskeletal protein expression, showed that each subpopulation progressed along unique developmental (differentiation) pathways, suggesting for each a genetically distinct developmental lineage. These subpopulations were shown to differ markedly from each other in their proliferation and matrix production responses to hypoxic pulmonary hypertension. Further, recent studies demonstrate that phenotypically distinct and stable SMC subpopulations, exhibiting marked differences in cell replication (in response to hypoxia and mitogens), can be isolated and maintained in culture. Preliminary data suggest that at least one of these subpopulations secretes a potent mitogen(s) for other SMC. We have recently identified one mitogen as Connective Tissue Growth Factor (CTGF), a factor not previously identified in the lung circulation. Important areas for investigation remain, including the mechanisms which a) confer unique growth properties to certain SMC populations, b) allow selective response to pathophysiologic stimuli, and c) influence communication between the subpopulations. The overall goal of our proposal is to investigate potential mechanisms that might confer a selective growth advantage to specific cell subpopulations in the vascular media, and to determine how the selective secretion of a specific mitogen (CTGF) by one cell subpopulation affects other cells in the media. Experiments are proposed to evaluate the hypothesis that augmented growth responses to mitogens and hypoxia in a phenotypically distinct subpopulation of cells within the vascular media is due, at least in part, to Gi-coupled receptors acting through the mitogen-activated protein kinase (MAPK) signaling system. In addition, experiments are proposed to test the hypothesis that CTGF is expressed by distinct subpopulations of cells in the vascular media during chronic hypoxia, and this expression is associated with the fibroproliferative changes observed in hypoxic pulmonary hypertension. Successful completion of the experiments proposed could provide new insight into the role distinct SMC populations might play in pulmonary vascular disease. A better understanding of the mechanisms contributing to cell proliferation in the SMC subpopulations actively contributing to the vascular remodeling process could lead to the development of improved therapeutic strategies to treat chronic pulmonary hypertension.
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