O 2 Sensing in the Human Ductus Arteriosus

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Abstract
Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by O 2 constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that O 2 alters the function of an O 2 sensor (the mitochondrial electron transport chain, ETC) thereby increasing production of a diffusible redox-mediator (H 2 O 2 ), thus triggering an effector mechanism (inhibition of DASMC voltage-gated K + channels, Kv). O 2 constriction was evaluated in 26 human DAs (12 female, aged 9±2 days) studied in their normal hypoxic state or after normoxic tissue culture. In fresh, hypoxic DAs, 4-aminopyridine (4-AP), a Kv inhibitor, and O 2 cause similar constriction and K + current inhibition ( I K ). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased O 2 and 4-AP constriction in DA rings and reduced O 2 - and 4-AP–sensitive I K in DASMCs. Remodeled DAMSCs are depolarized and express less O 2 -sensitive channels (including Kv2.1, Kv1.5, Kv9.3, Kv4.3, and BK Ca ). Kv2.1 adenoviral gene-transfer significantly reverses ionic remodeling, partially restoring both the electrophysiological and tone responses to 4-AP and O 2 . In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing I K and reversing constriction to O 2 , but not phenylephrine. O 2 increases, whereas hypoxia and ETC inhibitors decrease H 2 O 2 production by altering mitochondrial membrane potential (ΔΨm). H 2 O 2 , like O 2 , inhibits I K and depolarizes DASMCs. We conclude that O 2 controls human DA tone by modulating the function of the mitochondrial ETC thereby varying ΔΨm and the production of H 2 O 2 , which regulates DASMC Kv channel activity and DA tone.