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. Author manuscript; available in PMC: 2017 Mar 21.

Published in final edited form as: Ann Neurol. 2016 Feb 10;79(3):387–403. doi: 10.1002/ana.24573

Timp3 haploinsufficiency protects against attenuated functional hyperemia and altered cerebral blood flow (CBF) autoregulation in TgNotch3^R169C mice, whereas genetic reduction or ablation of vitronectin has no effect. CBF changes evoked by whisker stimulation (functional hyperemia; A, C, E) and controlled mean arterial pressure (MAP) reduction (B, D, F) were assessed in various 6-month-old transgenic mouse models (n = 5–8 males per genotype). (A, B) Single transgenic TgNotch3^R169C (TgN3^R169C) and TgNotch3^WT (TgN3^WT) mice, and nontransgenic (nonTg) littermate controls. (C, D) Double-mutant TgN3^R169C; Timp3⁺^/⁻ mice, with Timp3 haploinsufficiency in the context of Notch3^R169C overexpression; nonTg;Timp3⁺^/⁺, nonTg;Timp3⁺^/⁻, and TgNotch3^R169C;Timp3⁺^/⁺ mice were included as controls. (E, F) Double-mutant TgN3^R169C;Vtn⁺^/⁻ and TgN3^R169C;Vtn⁻^/⁻ mice, with vitronectin haploinsufficiency and complete ablation, respectively, in the context of Notch3^R169C overexpression; non-Tg;Vtn⁺^/⁺, nonTg;Vtn⁺^/⁻, nonTg;Vtn⁻^/⁻, and TgNotch3^R169C;Vtn⁺^/⁺ mice were included as controls. Functional hyperemia was strongly attenuated in TgN3^R169C mice compared to TgN3^WT and nonTg littermate mice, and TgN3^R169C mice showed an impaired relationship between CBF and MAP; CBF was significantly different between TgN3^R169C and TgN3^WT or nonTg mice at MAP values of 60 to 70mmHg. CBF responses were similarly impaired in TgN3^R169C mice expressing wild-type Timp3 (TgN3^R169C;Timp3⁺^/⁺) or wild-type vitronectin (TgN3^R169C;Vtn⁺^/⁺), whereas these responses were not altered in nonTg littermate mice with or without genetic reduction of Timp3 (nonTg;Timp3⁺^/⁻) or vitronectin (nonTg;Vtn⁻^/⁻). Importantly, TgN3^R169C;Timp3⁺^/⁻ mice exhibited normalized CBF responses to whisker stimulation and a restored relationship between MAP and CBF comparable to that of their nonTg;Timp3⁺^/⁻ and nonTg;Timp3⁺^/⁺ littermates (C, D). In contrast, neither TgN3^R169C;Vtn⁺^/⁻ nor TgN3^R169C;Vtn⁻^/⁻ mice (E, F) exhibited improved CBF responses. (A, C, E) One-way analysis of variance (ANOVA) followed by Tukey post hoc test; (B, D, F) 2-way repeated measures ANOVA followed by Bonferroni post hoc test (*p < 0.05). The main physiological variables for all mice are presented in the Table. ns = nonsignificant.