The relative expression of α1- and α 2-Na+/K+-ATPase isoforms found in vascular smooth muscle is developmentally regulated and under hormonal and neurogenic control. The physiological roles of these isoforms in vascular function are not known. It has been postulated that the α1-isoform serves a "housekeeping" role, whereas the α2-isoform localizes to a subsarcolemmal compartment and modulates contractility. To test this hypothesis, isoform-specific gene-targeted mice in which the mRNA for either the α1- or the α2-Na+/K +-ATPase isoform was ablated were utilized. Both of these knockouts, α1-/- and α2-/-, are lethal; the latter dies at birth, which allows this neonatal aorta to be studied. Isometric force in α2-/--aorta was more sensitive to contractile agonists and less sensitive to the vasodilators forskolin and sodium nitroprusside (SNP) than wild-type (WT) aorta; α 2+/--aortas had intermediate values. In contrast, neonatal α1+/--aorta was similar to WT. Western blot analysis indicated a population of 70% α1- and 30% α2-isoforms in the WT. Thus in terms of the total Na +/K+-ATPase protein, the α2 -/--aorta (at 70%) would be similar to the α1 +/--aorta (at 65%) but with a dramatically different phenotype. These data suggest that individual α-isoforms of the Na+/K +-ATPase differ functionally and that the α 2-isoform couples more strongly to activation-relaxation pathways. Three-dimensional image-acquisition and deconvolution analyses suggest that the α2-isoform is distributed differently than the α 1-isoform. Importantly, these isoforms do not localize to the same regions.
ASJC Scopus subject areas
- Cell Biology