title: WNK1 regulates vasoconstriction and blood pressure response to α 1-adrenergic stimulation in mice.
abstract: Gain-of-function mutations in the human WNK1 (with-no-lysine[K]1) gene are responsible for a monogenic form of arterial hypertension, and WNK1 polymorphisms have been associated with common essential hypertension. The role of WNK1 in renal ionic reabsorption has been established, but no investigation of its possible influence on vascular tone, an essential determinant of blood pressure, has been performed until now. WNK1 complete inactivation in the mouse is embryonically lethal. We, thus, examined in Wnk1(+/-) haploinsufficient adult mice whether WNK1 could regulate in vivo vascular tone and whether this was correlated with blood pressure variation. Wnk1(+/-) mice displayed a pronounced decrease in blood pressure responses in vivo and in vascular contractions ex vivo following α(1)-adrenergic receptor activation with no change in basal blood pressure and renal function. We also observed a major loss of the pressure-induced contractile (myogenic) response in Wnk1(+/-) arteries associated with a specific alteration of the smooth muscle cell contractile function. These alterations in vascular tone were associated with a decreased phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na(+)-K(+)-2Cl(-) cotransporter 1) in Wnk1(+/-) arteries. Our study identifies a novel and major role for WNK1 in maintaining in vivo blood pressure and vasoconstriction responses specific to α(1)-adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking α(1)-adrenergic receptors and pressure to WNK1, SPAK, and NKCC1 and may, thus, significantly broaden the comprehension of the regulatory mechanisms of vascular tone in arterial hypertension.
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center PARCC, 56 rue Leblanc, 75015 Paris, France. sonia.bergaya@inserm.fr
authors.forename: Sonia
authors.initials: S
authors.lastname: Bergaya
authors.forename: Sébastien
authors.initials: S
authors.lastname: Faure
authors.forename: Véronique
authors.initials: V
authors.lastname: Baudrie
authors.forename: Marc
authors.initials: M
authors.lastname: Rio
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonnin
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Achard
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D015153:Blotting, Western; D002339:Carotid Arteries / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D057895:Haploinsufficiency; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D015778:Minor Histocompatibility Antigens; D018340:Receptors, Adrenergic, alpha-1; C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse; D009638:Norepinephrine