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1 Department of Pediatrics, Northwestern University Medical School, Chicago, IL, USA
2 Department of Pediatrics, University of California, San Francisco, CA, USA; The Cardiovascular Research Institute, University of California, San Francisco, CA, USA
3 Department of Pediatrics, Northwestern University Medical School, Chicago, IL, USA; Department of Molecular Pharmaclogy, Northwestern University Medical School, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: steveblack{at}northwestern.edu.
Endothelial NO synthase (eNOS) mRNA and protein levels increase during late gestation and then decrease postnatally in sheep lung parenchyma. The increase in fluid shear stress at birth, resulting from increased pulmonary blood flow, is an important mediator of postnatal eNOS gene expression. The objective of this study was to identify factors that stimulate eNOS expression in pulmonary arterial endothelial cells (PAEC) in response to shear stress, and to determine if these factors are developmentally regulated. PAEC were isolated from fetal lambs and adult sheep. Transcriptional activity from a 1600bp eNOS promoter fragment increased in both fetal and adult PAEC exposed to 8 hours of shear stress. Conversely, activity driven from an 840bp promoter fragment containing a putative AP-1 binding site was increased only in fetal PAEC. This increase was completely abolished in an identical construct containing a mutant AP-1 sequence. The AP-1 protein c-jun was localized to the cytosol in static adult PAEC and to the nucleus in static fetal PAEC. After shear, c-jun was nuclear localized in both cell types. However, transcriptionally active phosphorylated c-jun was elevated only in the nuclei of sheared fetal PAEC. Resting levels of eNOS and NO were 2-fold and 20-fold higher respectively in fetal cells. Shear increased eNOS and NO in both cell types such that levels were approximately 2.5-fold higher in fetal PAEC. Phosphorylation of Akt and eNOS was evident in sheared fetal, but not adult PAEC. We have therefore identified mechanisms of eNOS regulation at the level of transcription and enzyme activation specific to the fetal pulmonary arterial circulation.
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