Letter by Dichgans et al Regarding Article, “Peripheral Artery Disease as a Manifestation of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) and Practical Implications”

Dichgans, Martin; Joutel, Anne; Chabriat, Hugues

doi:10.1161/circulationaha.113.003657

Cited by 2 publications

(1 citation statement)

References 5 publications

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“…Some CADASIL-mutated NOTCH3 receptors show reduced signaling, 18,19,40 and patients with CADASIL have fragile vasculature, such that angiographic analysis is avoided. 41 This is in line with the link between loss of Notch3 activity and the aneurysm-like changes and focal BBB leakage observed in this study. Similarly, the accumulation of fibrin observed here is of interest as vascular fibrin accumulation is well documented in patients with CADASIL 42,43 and could be a common downstream consequence of both degeneration or deregulation of VSMC.…”

Section: Possible Implications For Cadasil Pathogenesissupporting

confidence: 91%

Notch3 Is Necessary for Blood Vessel Integrity in the Central Nervous System

Henshall

Keller

et al. 2015

ATVB

117

133

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Objective— Vascular smooth muscle cells (VSMC) are important for contraction, blood flow distribution, and regulation of blood vessel diameter, but to what extent they contribute to the integrity of blood vessels and blood–brain barrier function is less well understood. In this report, we explored the impact of the loss of VSMC in the Notch3 −/− mouse on blood vessel integrity in the central nervous system. Approach and Results— Notch3 −/− mice showed focal disruptions of the blood–brain barrier demonstrated by extravasation of tracers accompanied by fibrin deposition in the retinal vasculature. This blood–brain barrier leakage was accompanied by a regionalized and patchy loss of VSMC, with VSMC gaps predominantly in arterial resistance vessels of larger caliber. The loss of VSMC appeared to be caused by progressive degeneration of VSMC resulting in a gradual loss of VSMC marker expression and a progressive acquisition of an aberrant VSMC phenotype closer to the gaps, followed by enhanced apoptosis and cellular disintegration in the gaps. Arterial VSMC were the only mural cell type that was morphologically affected, despite Notch3 also being expressed in pericytes. Transcriptome analysis of isolated brain microvessels revealed gene expression changes in Notch3 −/− mice consistent with loss of arterial VSMC and presumably secondary transcriptional changes were observed in endothelial genes, which may explain the compromised vascular integrity. Conclusions— We demonstrate that Notch3 is important for survival of VSMC, and reveal a critical role for Notch3 and VSMC in blood vessel integrity and blood–brain barrier function in the mammalian vasculature.

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