title: Inwardly rectifying K+channels are major contributors to flow-induced vasodilatation in resistance arteries.
abstract: Endothelial inwardly rectifying K+(Kir2.1) channels regulate flow-induced vasodilatation via nitric oxide (NO) in mouse mesenteric resistance arteries. Deficiency of Kir2.1 channels results in elevated blood pressure and increased vascular resistance. Flow-induced vasodilatation in human resistance arteries is also regulated by inwardly rectifying K+channels. This study presents the first direct evidence that Kir channels play a critical role in physiological endothelial responses to flow.
  
  
  
  Inwardly rectifying K+(Kir) channels are known to be sensitive to flow, but their role in flow-induced endothelial responses is not known. The goal of this study is to establish the role of Kir channels in flow-induced vasodilatation and to provide first insights into the mechanisms responsible for Kir signalling in this process. First, we establish that primary endothelial cells isolated from murine mesenteric arteries express functional Kir2.1 channels sensitive to shear stress. Then, using the Kir2.1+/-heterozygous mouse model, we establish that downregulation of Kir2.1 results in significant decrease in shear-activated Kir currents and inhibition of endothelium-dependent flow-induced vasodilatation (FIV) assayed in pressurized mesenteric arteries pre-constricted with endothelin-1. Deficiency in Kir2.1 also results in the loss of flow-induced phosphorylation of eNOS and Akt, as well as inhibition of NO generation. All the effects are fully rescued by endothelial cell (EC)-specific overexpression of Kir2.1. A component of FIV that is Kir independent is abrogated by blocking Ca2+-sensitive K+channels. Kir2.1 has no effect on endothelium-independent and K+-induced vasodilatation in denuded arteries. Kir2.1+/-mice also show increased mean blood pressure measured by carotid artery cannulation and increased microvascular resistance measured using a tail-cuff. Importantly, blocking Kir channels also inhibits flow-induced vasodilatation in human subcutaneous adipose microvessels. Endothelial Kir channels contribute to FIV of mouse mesenteric arteries via an NO-dependent mechanism, whereas Ca2+-sensitive K+channels mediate FIV via an NO-independent pathway. Kir2 channels also regulate vascular resistance and blood pressure. Finally, Kir channels also contribute to FIV in human subcutaneous microvessels.
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Ahn
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, USA.|Department of Physical Therapy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Ibra S
authors.initials: IS
authors.lastname: Fancher
authors.affiliation: Department of Physical Therapy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Jing-Tan
authors.initials: JT
authors.lastname: Bian
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Chong Xu
authors.initials: CX
authors.lastname: Zhang
authors.affiliation: Department of Physical Therapy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schwab
authors.affiliation: Department of Physiology, Physiology Core Lab, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Gaffin
authors.affiliation: Department of Physical Therapy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Phillips
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Irena
authors.identifier: 0000-0003-3072-6497
authors.initials: I
authors.lastname: Levitan
mesh_terms: D000328:Adult; D000818:Animals; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology*; D008822:Mice, Transgenic; D055806:Microvessels / Q000502:physiology; D008875:Middle Aged; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
chemical_list: C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying
keywords: K+ channels; endothelial cells; flow-induced vasodilation