Vascular Smooth Muscle Signaling in Intermittent Hypoxia-Induced Pulmonary Hypertension

University Of New Mexico Health Scis Ctr, Albuquerque NM

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Abstract

PROJECT SUMMARY Pulmonary vascular dysfunction resulting from chronic intermittent hypoxia (CIH) leads to pulmonary hypertension (pHTN) in patients with sleep apnea. Despite the growing recognition, prevalence, and impact of this disorder, the mechanisms involved in this response are poorly understood. The overall objective of the current study is to identify vascular smooth muscle (VSM) signaling mechanisms responsible for PKC?-mediated pulmonary vasoconstriction, and the role of this signaling pathway in CIH-dependent increases in vasoconstrictor reactivity, arterial remodeling and pHTN. Based on preliminary data, our guiding hypothesis is that PKC? mediates pulmonary vasoconstriction through a novel mechanism involving interaction with the scaffolding protein PICK1, activation of mitochondrial KATP (mitoKATP) channels, mitochondrial ROS (mitoROS) generation, and actin polymerization. Furthermore, we hypothesize that this signaling axis mediates enhanced vasoconstrictor reactivity, arterial remodeling and pHTN following CIH. We plan to test these hypotheses by pursuing the following specific aims: 1. Determine the role of PKC??mitoROS signaling in enhanced arterial constrictor reactivity and pulmonary hypertension following CIH. Hypothesis: The PKC?/mitoROS signaling axis contributes to the progression and maintenance of CIH- induced pHTN through contractile and mitogenic actions in VSM. 2. Define the signaling mechanism by which PKC? stimulates mitoROS generation in pulmonary VSM and increased vasoconstrictor sensitivity after CIH. Hypothesis: CIH enhances agonist-dependent pulmonary vasoconstriction via PICK1-dependent activation of mitoKATP channels and subsequent mitoROS production 3. Establish the contribution of actin polymerization to PKC?-induced VSM contraction and the role of this mechanism in augmented pulmonary arterial vasoconstrictor reactivity following CIH. Hypothesis: CIH augments agonist-induced pulmonary VSM Ca2+ sensitization and vasoconstriction through PKC? and mitoROS-dependent actin polymerization. We anticipate that this project will define an innovative paradigm of VSM signaling involving PKC?, mitoROS generation, actin polymerization and Ca2+ sensitization that is unique to the pulmonary circulation, and the role of this pathway in the development of pHTN in a clinically relevant rodent model of sleep apnea. These studies are significant because they are expected to vertically impact our understanding of vasoconstrictor mechanisms that contribute to CIH-induced pHTN, and therefore have potential to yield unique treatment strategies for sleep apnea-associated pHTN and other cardiovascular and metabolic disorders in which PKC? signaling is a central player.