Idiopathic pulmonary hypertension (PH) is associated with progressive pulmonary vascular obliterative disease (PVOD) in otherwise healthy children and young adults. Some patients have an underlying genetic mutation causing loss of function of bone morphogenetic protein receptor II (BMP-RII) and some others have polymorphisms leading to heightened activity of the serotonin transporter (SERT). How these genetic abnormalities cause PVOD, is, however, unclear. Our recent studies in cultured human pulmonary artery (PA) smooth muscle cells (SMC) have shown that serotonin, likely in conjunction with SERT, increases expression of the calcium binding protein S100A4/Mts1 (Mts1). We further observed that recombinant Mts1 induces motility of PA SMC. Consistent with this, intense expression of Mts1 is apparent in PVOD in clinical tissue, in contrast to minimal expression in normal vessels. Also, 5-10% of transgenic mice that over-express Mts1 acquire PVOD as they age and all Mts1 overexpressing mice develop more severe PH than controls during hypoxia that does not regress with return to normoxia. Microarray analysis of DNA in lungs from Mts1 over-expressing vs. control mice shows a reduction in BMP-RI, the co-receptor of BMP-RII. We therefore propose that there are common and complementary molecular pathways linking BMP-RII, SERT and Mts1 in the pathophysiology of PVOD.
Specific Aim I utilizes a variety of tools including short interference (si) RNA in cultured human PA endothelial and SMC to determine how BMP-RII, SERT and Mts1 might impact on vascular remodeling, either by inducing elastase activity and/or by promoting cell migration, proliferation, transdifferentiation, or propensity or resistance to apoptosis. These features will be correlated with the function of the transcription factor AML1, and with the genomic profiles of the cells.
In Specific Aim II, transgenic mice with Mts1 over-expression will be investigated with respect to vascular reactivity and severity of PH in response to dexfenfluramine or inflammation. We also will produce and characterize a mouse with conditional global or SMC targeted deletion of BMP-RII, in terms of vascular cell structure, function, and propensity to PH. Genomic data from lung, endothelial and SMC from Mts1 over-expressing, BMP-RII deleted, and control mice will be correlated with function to identify common and complementary gene expression patterns related to PVOD. These studies should provide insights into the genetic basis for PVOD and information useful in developing strategies to arrest or reverse the process.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Physiology Study Section (RESP)
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Denholm, Elizabeth M
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Stanford University
Schools of Medicine
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