Aarhus Universitets segl

The NA,K-ATPase dependent signaling pathway is associated with vascular abnormalities

Projekter: ProjektForskning

Se relationer på Aarhus Universitet


The Na,K-ATPase is essential for maintaining the transmembrane ion gradients required for
normal cell function. Previous studies clearly indicate that a specific Na,K-ATPase inhibitor,
ouabain can initiate Src kinase signaling independently of the effects on ATPase mediated ion
translocation. This Na,K-ATPase-Src signaling has been shown in the kidney and heart, and
seems perfectly suited for modulation of vasoconstriction, but has never been studied in smooth
Several findings indirectly suggest the importance of Na,K-ATPase-Src complex for vascular
remodeling and elevated contraction in resistance arteries in ouabain-induced and other forms of
hypertension. Familial hemiplegic migraine type 2 (FHM2) associated with the loss-of-function
mutation in the Na,K-ATPase, is characterized by elevated vascular contractility which might
depend on Src activation.
We suggest that the Na,K-ATPase-dependent Src activation could increase arterial contraction
via sensitization of the contractile machinery to intracellular Ca2+, modulation of gene
expression and smooth muscle cell phenotype.
We aim to test the hypothesis that the Na,K-ATPase-Src complex is an important modulator for
vascular structure and function. We will study in vitro and in vivo the significance of this
complex for development of hypertension and vascular abnormalities associated with Na,KATPase-
dependent migraine.
We will induce ouabain-dependent hypertension in rodents and use mice bearing the Na,KATPase
mutation characteristic for FHM2. The effect of specific inhibitors of Na,K-ATPasedependent
Src activation on blood pressure and resistance arteries structure and function will be
studied. The Na,K-ATPase-Src signaling cascade will be characterized at the molecular level.
The novel signaling initiated from the Na,K-ATPase in the vascular wall could be of substantial
physiological significance and increase our understanding of the mechanisms of hypertension
and provide a new antihypertensive target.
Effektiv start/slut dato01/01/201531/12/2017


ID: 129032989