Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral ArteriesNovelty and Significance [Vessels]

In this study, we investigated the contribution of TIMP3 and Notch3 signaling to the impairment of maximal vasodilator capacity caused by the archetypal R169C mutation. Maximally dilated cerebral arteries in TgNotch3R169C mice exhibited a decrease in lumen diameter over a range of physiological pressures that occurred before myogenic tone deficits. This defect was not prevented by genetic reduction of TIMP3 in TgNotch3R169C mice and was not observed in mice overexpressing TIMP3. Knock-in mice with the R169C mutation (Notch3R170C/R170C) exhibited similar reductions in arterial lumen, and both TgNotch3R169C and Notch3R170C/R170C mice showed increased cerebral artery expression of Notch3 target genes. Reduced maximal vasodilation was prevented by conditional reduction of Notch activity in smooth muscle of TgNotch3R169C mice and mimicked by conditional activation of Notch3 in smooth muscle, an effect that was blood pressure–independent. We conclude that increased Notch3 activity mediates reduction in maximal dilator capacity of cerebral arteries in CADASIL and may contribute to reductions in cerebral blood flow.

Source: Hypertension - December 6, 2016 Category: Cardiology Authors: Celine Baron–Menguy, Valerie Domenga–Denier, Lamia Ghezali, Frank M. Faraci, Anne Joutel Tags: Animal Models of Human Disease, Pathophysiology, Genetically Altered and Transgenic Models, Vascular Disease Original Articles Source Type: research