Signaling through the bone morphogenetic protein (BMP) pathway is essential to organ developments. In this dissertation, two aspects of the BMP pathway were studied: downstream targets and extracellular regulators of BMP signaling. To identify downstream BMP mediators in angiogenesis, we performed microarray analysis on endothelial cells (ECs) treated with BMP6 and identified cyclooxygenase 2 (Cox2) as a potential target of BMP6. Upregulation of Cox2 as detected in the microarray was confirmed at the transcriptional level by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and by reporter assays. BMP6-induced endothelial cell proliferation, migration and tube formation activities were all blocked by selective pharmacologic inhibition of Cox2. Both genetic deletion and pharmacologic inhibition of Cox2 markedly attenuated BMP6-dependent angiogenesis in an aortic ring assay. Targeted deletion of BMP-binding endothelial precursor-derived regulator (Bmper), encoding an extracellular regulator of BMP signaling, demonstrates its essential role as a BMP signal controller in early development. Among other phenotypes, loss of Bmper activity caused abnormal branching morphogenesis in the lung and induced hypertrophy in cardiomyocytes. Transcriptional analysis using quatititive real-time PCR revealed the upregulation of hypertrophy markers and BMP signals in Bmper knockout cardiomyocytes and is consistent with a protective role for Bmper in cardiac hypertrophy via the downregulation of BMP pathway components. In summary, this research implicates that both BMP downstream mediators and their extracellular regulators as potential therapeutic targets in physiopathological events associated with abnormal BMP activities
