Abstract 37: Deletion of Notch3 Gene Impairs Contractility of Renal Resistance Vessels
Background: Notch3 plays an important role in the differentiation and development of vascular smooth muscle cells. In previous studies we showed that mice lacking Notch3 display deficient renal autoregulation.
Objective: Our aim was to study the mechanisms involved in the Notch3-mediated control of renal vascular response.
Methods and Results: To this end, renal afferent arterioles were isolated from Notch3-/- and wild type littermates and stimulated with ANG II. Contractions and intracellular Ca2+ concentrations were blunted in Notch3-/- vessels in a dose-dependent manner (diameter decrease: 15±3 vs. 38±5%, p<0.01; change of fura 2 ratio: 0.18±0.02 vs. 0.39±0.05, p<0.001, at 10-7Ang II for Notch3-/- and wt vessels, respectively). Differential transcriptomic analysis of 47 genes known to participate in vasoreactivity indicated an important downregultion of the cacna1h gene expressing the α1H subunit of the T-type Ca2+ channel in the renal vessels of Notch3-/- mice. This finding was confirmed by real-time qPCR and western blotting. In subsequent experiments, addition of EGTA (Ca2+ chelating agent), nifedipine (L-type channel blocker) or mibefradil (T-type channel blocker) blunted as expected the response to ANG II in wild-type vessels. In sharp contrast, these agents did not affect vessel responsiveness in Notch3-/- indicating dysfunctional extracellular Ca2+-entry. Abolishing stored Ca2+ with thapsigargine, reduced Ca2+ responses equally in both strains, signifying intact Ca2+-mobilization in Notch3-/- vessels. In contrast to renal resistance vessels, pre-capillary muscle arterioles of Notch3-/- mice reacted normally to ANG II, suggesting a focal role of Notch3 in the renal vasculature.
Conclusions: Notch3-/- mice display deficient renal vascular reactivity because of blunted expression and function of calcium channels. Consequently, intact Notch3 expression is necessary for proper regulation of renal vascular tone in the kidney, whereas dysfunction of Notch3 can have important physiopathological consequences by impairing regulation of renal hemodynamics
- © 2012 by American Heart Association, Inc.