Valproate Limits Vascular Remodeling and Protects Against Memory Deficits Following Chronic Hypoperfusion
Authors: Lansdell Teri A , Yen Martina , Dorrance Anne M 
Published: April 2020

Background and Purpose

Chronic cerebral hypoperfusion is a risk factor for vascular cognitive impairment. Bilateral carotid artery stenosis (BCAS), a physiologically relevant model of chronic cerebral hypoperfusion, produces damage to the deep white matter of the brain with corresponding deficits in working memory. BCAS increases histone deacetylase (HDAC) activity and global histone acetylation changes in rat brains which may play a role in smooth muscle cell phenotypic changes and vascular remodeling. We tested the hypothesis that treatment of BCAS rats with the HDAC inhibitor, valproate (VPA), limits remodeling and protect rats from memory deficits.

Methods

Twenty female Sprague Dawley rats age 16–20 weeks old were subjected to either sham or BCAS surgery and treated with either 300 mg/kg/day VPA or vehicle for eight weeks. Cognitive function was assessed using the novel object recognition test. Rats were subjected to laser speckle imaging to determine cerebral blood flow and then euthanized. Gene expression of HDAC9, ACTA2 and Ki67was measured in the basilar artery using qPCR. All data are reported as the mean ± the standard error (n=5 per group). All experiments were analyzed using one‐way ANOVA with a Bonferoni correction. P‐values of less than 0.05 were considered significant.

Results

As expected, there was no significant difference in cerebral perfusion between the sham‐vehicle and the BCAS‐vehicle groups at euthanasia. Furthermore, treatment of the rats with VPA had no effect on cerebral perfusion. HDAC expression in the basilar artery of BCAS‐vehicle rats was increased compared to sham‐vehicle rats (1.6 ± 0.2 vs. 1.0 ± 0.1, P=0.0161) and HDAC expression in BCAS‐VPA rats was restored to the sham‐vehicle treated levels (0.9 ± 0.1 vs. 1.0 ± 0.1). Increased ACTA2 expression is a marker for hypertrophy due to hemodynamic stress and was increased in the basilar artery of BCAS‐vehicle rats compared to sham‐vehicle rats (2.3± 0.8 vs. 1.0 ± 0.1, P=0.0494). While VPA had no effect on ACTA2 expression in the sham‐VPA rats, ACTA2 expression in the basilar arteries of BCAS‐VPA rats was restored to the sham‐vehicle levels (0.9 ± 0.3 vs. 1.0 ± 0.1). MKI67 expression was unchanged in BCAS‐vehicle compared to the sham‐vehicle rats while the proliferative marker was increased in the BCAS‐VPA treated rats compared to the sham‐vehicle (3.2 ± 0.7 vs. 1.5 ± 0.4, P=0.0409) and to the BCAS‐vehicle rats (3.2 ± 0.7 vs. 1.3 ± 0.3, P=0.0298). Novel object exploration tests indicate that BCAS‐vehicle rats explored the novel object 29.4 ± 7.1% less than sham‐vehicle rats (P=0.0186) while BCAS‐VPA rats appeared protected from memory impairment and explored the novel object the same amount as the sham‐vehicle rats.

Conclusion and future directions

VPA treatment results in decreased expression of hypertrophic markers and is associated with functional restoration of working memory in BCAS rats with white matter injury caused by BCAS. There is a translational potential for clinically used HDAC inhibitors in the treatment of vascular cognitive impairment. Future work will focus on determining sex differences in the response to BCAS and treatment with VPA as well as quantifying white matter injury, and vessel density within the cortex.

Support or Funding Information

The Brain Aneurysm Foundation Research Award