At birth, ventilation and oxygenation immediately produce a dramatic decrease in pulmonary vascular resistance and an increase in pulmonary blood flow with more gradual changes occurring over the next several hours. Nitric oxide (NO), produced from L-arginine by endothelial nitric oxide synthase (eNOS), appears to mediate, at least in part, these gradual changes. Aberrations in NO activity have also been implicated in the pathophysiology of disease states such as persistent pulmonary hypertension of the newborn (PPHN). The mechanism producing the increased NO activity at birth remains unknown. Our overall goals are to determine the factors that regulate pulmonary blood flow and pulmonary vascular resistance at the fetal to newborn transition. The increases in pulmonary blood flow occurring at birth will likely produce an increase in the shear forces on the pulmonary vascular endothelium. NO production, NOS activity, eNOS mRNA and protein expression are increased when endothelial cells (ECS) are exposed to increased shear stress. We hypothesize that the increased shear forces to which the pulmonary system is exposed to after birth will produce an increase in eNOS gene expression; subsequently, this leads to the gradual decrease in PVR and the increased PBF seen in the first several hours after birth. To allow a molecular analysis of the effects of birth on the fetal pulmonary endothelium we have isolated and cultured the relevant late gestation ovine pulmonary arterial ECs. To mimic the effects of increased blood flow we have built a cone-plate viscometer which allows us to expose the EC monolayer to a controlled level of shear stress. We have also cloned the promoter region of the human eNOS gene upstream of a Luciferase reporter. We will use this to identify the DNA sequences within the eNOS promoter (cis-elements) that are activated by shear stress in fetal pulmonary arterial ECs. This may eventually lead to the identification of transcription (transacting) factors responsible for the increase in eNOS gene expression during the transition from fetal to neonatal life.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060190-04
Application #
6194840
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$103,120
Indirect Cost
Name
Northwestern University at Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Whitaker, Morgan E; Nair, Vineet; Sinari, Shripad et al. (2018) Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension. Am J Med 131:702.e7-702.e13
Wang, Ting; Gross, Christine; Desai, Ankit A et al. (2017) Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets. Am J Physiol Lung Cell Mol Physiol 312:L452-L476
Suratt, Benjamin T; Ubags, Niki D J; Rastogi, Deepa et al. (2017) An Official American Thoracic Society Workshop Report: Obesity and Metabolism. An Emerging Frontier in Lung Health and Disease. Ann Am Thorac Soc 14:1050-1059
Song, Shanshan; Ayon, Ramon J; Yamamura, Aya et al. (2017) Capsaicin-induced Ca2+ signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH. Am J Physiol Lung Cell Mol Physiol 312:L309-L325
Chen, F; Wang, Y; Rafikov, R et al. (2017) RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G+-bacterial toxins. Biochem Pharmacol 127:34-45
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Kovacs, Laszlo; Han, Weihong; Rafikov, Ruslan et al. (2016) Activation of Calpain-2 by Mediators in Pulmonary Vascular Remodeling of Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 54:384-93
Sharma, Bal Krishan; Kolhe, Ravindra; Black, Stephen M et al. (2016) Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. FASEB J 30:262-75

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