Deletion of Notch3 Impairs Contractility of Renal Resistance Vessels Due to Deficient Ca2+ Entry - Sorbonne Université Access content directly
Journal Articles International Journal of Molecular Sciences Year : 2022

Deletion of Notch3 Impairs Contractility of Renal Resistance Vessels Due to Deficient Ca2+ Entry

Abstract

Notch3 plays an important role in the differentiation and development of vascular smooth muscle cells. Mice lacking Notch3 show deficient renal autoregulation. The aim of the study was to investigate the mechanisms involved in the Notch3-mediated control of renal vascular response. To this end, renal resistance vessels (afferent arterioles) were isolated from Notch3−/− and wild-type littermates (WT) and stimulated with angiotensin II (ANG II). Contractions and intracellular Ca2+ concentrations were blunted in Notch3−/− vessels. ANG II responses in precapillary muscle arterioles were similar between the WT and Notch3−/− mice, suggesting a focal action of Notch3 in renal vasculature. Abolishing stored Ca2+ with thapsigargin reduced Ca2+ responses in the renal vessels of the two strains, signifying intact intracellular Ca2+ mobilization in Notch3−/−. EGTA (Ca2+ chelating agent), nifedipine (L-type channel-blocker), or mibefradil (T-type channel-blocker) strongly reduced contraction and Ca2+ responses in WT mice but had no effect in Notch3−/− mice, indicating defective Ca2+ entry. Notch3−/− vessels responded normally to KCl-induced depolarization, which activates L-type channels directly. Differential transcriptomic analysis showed a major down-regulation of Cacna1h gene expression, coding for the α1H subunit of the T-type Ca2+ channel, in Notch3−/− vessels. In conclusion, renal resistance vessels from Notch3−/− mice display altered vascular reactivity to ANG II due to deficient Ca2+-entry. Consequently, Notch3 is essential for proper excitation–contraction coupling and vascular-tone regulation in the kidney.
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Dates and versions

hal-03922921 , version 1 (04-01-2023)

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Frank Helle, Michael Hultström, Panagiotis Kavvadas, Bjarne Iversen, Christos E Chadjichristos, et al.. Deletion of Notch3 Impairs Contractility of Renal Resistance Vessels Due to Deficient Ca2+ Entry. International Journal of Molecular Sciences, 2022, 23 (24), pp.16068. ⟨10.3390/ijms232416068⟩. ⟨hal-03922921⟩
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