Pulmonary hypertension (PH) is a significant source of morbidity and mortality in infants. Although vasoconstriction is widely recognized as a critical mediator of neonatal PH, little is known regarding mechanisms of vasoconstriction in this setting, and current vasodilator therapies are largely ineffective. The overall objective of the current application is to identify vascular smooth muscle (VSM) signaling mechanisms responsible for PKC-mediated pulmonary vasoconstriction, and the role of this signaling pathway in chronic hypoxia (CH)-dependent increases in vasoconstrictor reactivity, arterial remodeling, and PH in neonates. Based on preliminary studies, our central hypothesis is that neonatal CH mediates spontaneous pulmonary arterial tone, enhanced agonist-induced pulmonary vasoconstrictor sensitivity, arterial remodeling and PH through PKC?-induced mitochondrial ROS (mitoROS) signaling in pulmonary VSM. The following specific aims will be pursued:
Specific Aim 1 : Define the signaling mechanism by which PKC? mediates enhanced basal tone and agonist-induced vasoconstrictor sensitivity following CH in neonates. Hypothesis: Neonatal CH augments pulmonary vasoconstrictor sensitivity via PKC? dependent activation of mitoROS generation and subsequent VSM myofilament Ca2+ sensitization.
Specific Aim 2 : Determine the role of PKC? signaling in the development of CH-induced neonatal PH. Hypothesis: The PKC?/mitoROS signaling axis contributes to the progression and maintenance of CH- induced PH in neonates through both contractile and mitogenic actions in VSM. To test these hypotheses, protocols will employ a variety of experimental preparations from single cell imaging to video-microscopy of pressurized small pulmonary arteries from control and CH neonatal rats. We will also determine the significance of PKC? and mitoROS to the development of neonatal PH. This research is innovative in its investigation of a novel signaling mechanism that is unique to the pulmonary circulation, and the role of this pathway in the development of CH-induced neonatal PH. This study is significant because it is expected to vertically impact our understanding of mechanisms that contribute to PH in the neonate, and therefore has potential to yield new treatment strategies for PH and other cardiovascular and metabolic disorders in which PKC? signaling is a central player.

Public Health Relevance

Pulmonary hypertension in infants causes significant morbidity involving poor blood oxygenation (hypoxia) that impairs neural development and leads to chronic lung disease. Neonatal pulmonary hypertension can also progress to respiratory distress and death. Little is known about the underlying causes of pulmonary hypertension in newborns and current therapies are met with limited success. The planned studies are relevant to the mission of the National Heart, Lung, and Blood Institute because they will mechanistically examine the contribution of a novel intracellular signaling pathway to pulmonary hypertension in infants using an animal model of neonatal pulmonary hypertension, and have potential to reveal new therapeutic targets of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HL131334-02
Application #
9233743
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20)L)
Program Officer
Colombini-Hatch, Sandra
Project Start
2016-02-01
Project End
2017-07-31
Budget Start
2017-02-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2017
Total Cost
$16,314
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Sheak, Joshua R; Weise-Cross, Laura; deKay, Ray J et al. (2017) Enhanced NO-dependent pulmonary vasodilation limits increased vasoconstrictor sensitivity in neonatal chronic hypoxia. Am J Physiol Heart Circ Physiol 313:H828-H838