Figure 4. PVM depletion restores BBB integrity and improves cognitive function in chronically hypertensive BPH/2J mice.
A. BPH/2J mice have elevated systolic BP as early as 8 weeks of age compared to normotensive BPN/3J controls (n=7-10; 2-way ANOVA, Bonferroni’s multiple comparisons test; *p<0.001). B. Enhanced leakage of FITC-Dextran is found in BPH/2J mice as early as 8 weeks of age (2-way ANOVA, Interaction p=0.6749, Age Factor p=0.2640, Genotype Factor p<0.0001; Bonferroni’s multiple comparison test: 8 weeks n=7-8 *p=0.0299; 12 weeks n=10-12 *p=0.0010; 24 weeks n=6-7 *p=0.0189; 36 weeks n=6-4 *p=0.0017). C. BPH/2J mice spend less time exploring a novel object starting at 12 weeks, and progressing through 36 weeks of age (2-way ANOVA, Interaction p<0.0001, Age Factor p=0.0009, Genotype Factor p<0.0001; Bonferroni’s multiple comparison test: 8 weeks n=9 p>0.9999; 12 weeks n=9 *p=0.0001; 24 weeks n=15-16 *p<0.0001; 36 weeks n=14-17 *p<0.0001). D. PVM depletion with liposomal clodronate (CLO) attenuates the BBB breakdown in BPH/2J mice (n n=8-11, 2-way ANOVA, Interaction p=0.0118, Liposome Factor p=0.0013, Genotype Factor p=0.0001; Bonferroni’s multiple comparison test: BPN-PBS vs BPH-PBS *p<0.0001, BPH-CLO vs BPH-PBS *p=0.0003). E. PVM depletion restores cognitive deficits assessed by novel object recognition test in BPH/2J mice (n=8-11, 2-way ANOVA, Interaction p=0.0022, Liposome Factor p=0.0030, Genotype Factor p<0.0001; Bonferroni’s multiple comparison test: BPN-PBS vs BPH-PBS *p<0.0001, BPH-CLO vs BPH-PBS *p=0.0002). F. PVM depletion restores the aversion toward the center area at the open-field test without affecting total ambulatory time in BPH/2J mice (n=8-11, 2-way ANOVA, Interaction p=0.0005, Liposome Factor p=0.0010, Genotype Factor p=0.0002; Bonferroni’s multiple comparison test: BPN-PBS vs BPH-PBS *p<0.0001, BPH-CLO vs BPH-PBS *p<0.0001).