| First Author | Baron-Menguy C | Year | 2017 |
| Journal | Hypertension | Volume | 69 |
| Issue | 1 | Pages | 60-70 |
| PubMed ID | 27821617 | Mgi Jnum | J:283127 |
| Mgi Id | MGI:6367938 | Doi | 10.1161/HYPERTENSIONAHA.116.08015 |
| Citation | Baron-Menguy C, et al. (2017) Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries. Hypertension 69(1):60-70 |
| abstractText | CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), the most frequent genetic cause of stroke and vascular dementia, is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle. The well-established TgNotch3(R169C) mouse model develops characteristic features of the human disease, with deposition of NOTCH3 and other proteins, including TIMP3 (tissue inhibitor of metalloproteinase 3), on brain vessels, as well as reduced maximal dilation, and attenuated myogenic tone of cerebral arteries, but without elevated blood pressure. Increased TIMP3 levels were recently shown to be a major determinant of altered myogenic tone. 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 TgNotch3(R169C) 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 TgNotch3(R169C) mice and was not observed in mice overexpressing TIMP3. Knock-in mice with the R169C mutation (Notch3(R170C/R170C)) exhibited similar reductions in arterial lumen, and both TgNotch3(R169C) and Notch3(R170C/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 TgNotch3(R169C) 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. |
