J026 A role for L-WNK1 in cardiovascular development and vasoconstriction

Abstract

Mutations at the WNK1 gene cause Gordon syndrome, a rare inherited form of arterial hypertension. The gene encodes a short kidney-specific isoform and a complete long isoform, L-WNK1, expressed ubiquitously and notably within the vascular system. The aim of our study was to investigate the vascular role of L-WNK1 in mice. We used mice bearing a constitutive homozygous inactivation of L-WNK1 (L-WNK1-/-) which die in utero before day 13 of gestation as well as adult healthy heterozygous (L-WNK1+/-) and wild-type (L-WNK1+/+) littermates. We isolated vessels from L-WNK1+/- and L-WNK1+/+ to perform in vitro pharmacological studies in a wire-myograph system and an arteriograph system. We first showed that L-WNK1-/- embryos present growth retardation and severe oedema. An abnormal vascular remodeling was observed at day 10.5 within the primary vascular network of L-WNK1-/- embryos as well as in the yolk sac, suggesting an important role of L-WNK1 in cardiovascular development. We next showed that vascular diameters of pressurized arteries as well as arterial blood flow velocities measured by echo-Doppler were comparable between L-WNK1+/- and L-WNK1+/+ mice. Endothelium-dependent dilatations induced either by acetylcholine or by flow were also comparable between both groups of mice. In contrast, phenylephrine-induced vasoconstrictions were significantly reduced in L-WNK1+/- mice compared to L-WNK1+/+ mice in thoracic aorta as well as in mesenteric arteries (27.45 % (P=0.04) and 39.6 % (P=0.0015) decrease at maximal concentration, respectively) whereas potassium chloride contractions remained comparable. Furthermore, myogenic tone in L-WNK1+/- mesenteric arteries was also significantly blunted when compared to L-WNK1+/+ mice (P<0.0001). Our results evidenced for the first time a vascular role for L-WNK1 in pressure- and agonist- induced contractions.