At birth, the pulmonary circulation changes dramatically. Pulmonary blood flow increases 8-10 fold while pulmonary arterial (PA) pressure declines. If the pulmonary circulation does not make the transition to a high flow, low pressure circuit, then persistent pulmonary hypertension of the newborn (PPHN) results. PPHN is characterized by increased pulmonary vascular tone and reactivity, resulting in severe central hypoxemia that responds incompletely to the administration of supplemental O2 and other vasodilator stimuli. Neither prevention nor cure is currently available. Treatment options are compromised by incomplete understanding of the mechanisms responsible for postnatal adaptation of the pulmonary circulation. While the acute increase in O2 tension is clearly an essential physiologic stimulus for pulmonary vasodilation in the perinatal period, the identity of the O2 sensor remains unknown. Thus, the mechanism whereby the perinatal pulmonary vasculature senses and vasodilates in response to the acute increase in O2 tension remains incompletely understood. Treatment strategies are compromised by the lack of molecular targets for therapy. This proposal seeks to determine whether the ability of the pulmonary vasculature to respond to an acute increase in O2 tension is developmentally regulated and the subcellular mechanisms that allow the perinatal pulmonary circulation to vasodilate in response to an increase in O2 tension. Evidence suggests that potassium (K+) channels in PA smooth muscle cells (SMC) act as the O2 sensor. Work from our laboratory suggests that the calcium-sensitive K+ (KCa) channel plays a central role in mediating the response of the perinatal pulmonary circulation to an acute increase in O2 tension. We propose the working HYPOTHESIS that oxygen activates a KCa channel through intracellular calcium release to cause PA SMC Em hyperpolarization, contributing to perinatal pulmonary vasodilation.
The specific aims are to test the following hypotheses:
Aim 1. The KCa channel is a major component of PA SMC O2 sensing in the late-gestation fetus and newborn and is developmentally regulated Aim 2. Activation of the PA SMC KCa channel through Ca2+ sparks contributes to perinatal pulmonary vasodilation. To test these hypotheses, we plan experiments using electrophysiology, dynamic calcium imaging, confocal microscopy, molecular biology, immunocytochemistry, and whole animal physiology. The experiments will provide definitive identification of an O2 sensor in the neonatal pulmonary circulation that may be developmentally regulated and elucidate the subcellular processes that lead to its activation, thereby providing a novel molecular target to address neonatal pulmonary vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060784-02
Application #
6184655
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$270,255
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Cornfield, David N (2016) Shifting the Paradigm in Hemolytic Uremic Syndrome. Pediatrics 137:
Cornfield, David N; Bhargava, Sumit (2015) Sleep medicine: pediatric polysomnography revisited. Curr Opin Pediatr 27:325-8
Ying, Lihua; Becard, Margaux; Lyell, Deirdre et al. (2015) The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy. Sci Transl Med 7:319ra204
Kim, Francis Y; Barnes, Elizabeth A; Ying, Lihua et al. (2015) Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 308:L368-77
Conrad, Carol; Cornfield, David N (2014) Pediatric lung transplantation: promise being realized. Curr Opin Pediatr 26:334-42
Kim, Yu-Mee; Barnes, Elizabeth A; Alvira, Cristina M et al. (2013) Hypoxia-inducible factor-1? in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation. Circ Res 112:1230-3
Ahn, Yong-Tae; Kim, Yu-Mee; Adams, Eloa et al. (2012) Hypoxia-inducible factor-1ýý regulates KCNMB1 expression in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 302:L352-9
Iosef, Cristiana; Alastalo, Tero-Pekka; Hou, Yanli et al. (2012) Inhibiting NF-?B in the developing lung disrupts angiogenesis and alveolarization. Am J Physiol Lung Cell Mol Physiol 302:L1023-36
Alvira, Cristina M; Umesh, Anita; Husted, Cristiana et al. (2012) Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production. Am J Respir Cell Mol Biol 47:669-78

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