WNK1 Regulates Vasoconstriction and Blood Pressure Response to α1-Adrenergic Stimulation in Mice
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 α1-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 α1-adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking α1-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.
- blood pressure
- conductance and resistive arteries
- vascular smooth muscle cell
- α1 adrenergic receptors
- myogenic response
- Received February 28, 2011.
- Revision received April 4, 2011.
- Accepted June 19, 2011.
- © 2011 American Heart Association, Inc.