Role of PKCbeta and oxidant signaling in neonatal pulmonary hypertension

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 DESCRIPTION (provided by applicant): 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 PKCβ-induced mitochondrial ROS (mitoROS) signaling in pulmonary VSM. The following specific aims will be pursued: Specific Aim 1: Define the signaling mechanism by which PKCβ mediates enhanced basal tone and agonist-induced vasoconstrictor sensitivity following CH in neonates. Hypothesis: Neonatal CH augments pulmonary vasoconstrictor sensitivity via PKCβ dependent activation of mitoROS generation and subsequent VSM myofilament Ca2+ sensitization. Specific Aim 2: Determine the role of PKCβ signaling in the development of CH-induced neonatal PH. Hypothesis: The PKCβ/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 PKCβ 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 PKCβ signaling is a central player.