Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus

Abstract

Background— Oxygen (O ₂ )-sensitive K ⁺ channels mediate acute O ₂ sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O ₂ -induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O ₂ constriction in preterm DA is reduced expression and function of O ₂ -sensitive, voltage-gated (Kv) channels. Methods and Results— Preterm rabbit DA rings have reduced O ₂ constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O ₂ -sensitive K ⁺ current. This is associated with decreased mRNA and protein expression of certain O ₂ -sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer “rescues” the developmental deficiency, conferring O ₂ responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O ₂ constriction in human DAs. Conclusions— These data demonstrate a central role for developmentally regulated DASMC O ₂ -sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O ₂ responsiveness, including persistent DA.