Soluble epoxide hydrolase inhibition in hypertensive rats improves cognitive function and hippocampal parenchymal arterial dilation in a sex-dependent manner

Vascular dementia (VD) accounts for 17-30% of dementia cases, making it the second most common subtype following Alzheimer’s disease. It's true prevalence, however, may be much higher, as cerebrovascular damage is found in 50% of Alzheimer’s patients post-mortem. Hypertension, a leading risk factor for VD, alters cerebral artery structure and function, this impairs blood flow regulation and leads to cognitive decline. Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acid (EETs), which are vasodilators, thus, sEH inhibition could enhance cerebral microvascular perfusion and reduce hypertension-associated cognitive deficits. We showed that chronic sEH inhibition improves cognitive function and parenchymal arterial (PA) dilation in a hypertensive model of chronic cerebral hypoperfusion. There are complex sex differences between hypertension and VD development, with the occurrence of dementia being higher in females than males. To explore the role of sEH in these differences, we hypothesized that in stroke prone spontaneously hypertensive rats (SHRSP), pharmacological inhibition of sEH with trifluoromethoxyphenyl-3 (1-propionylpiperidin-4-yl) urea (TPPU) improves cognitive function and hippocampal PA (HPA) dilation in males and females. 20-week-old SHRSP were treated with vehicle or TPPU for 8 weeks. HPA dilation and structure were assessed by pressure myography. Resting cerebral perfusion was measured using laser speckle contrast imaging. Cognitive function was assessed by novel object recognition. Blood pressure was measured by tail-cuff plethysmography. Data are presented as means ± SEM (n=4-8). HPA data are presented at an intraluminal pressure of 60 mmHg. In male SHRSP, TPPU improved endothelium-dependent dilation in response to the TRPV4 agonist GSK1016790A (10 -9 -10 -5 M) (Vehicle: 22.2 ± 6.1; TPPU: 70.2 ± 6.5; p=0.0019) and the nonselective activator of small- and intermediate-Ca 2+ -activated K + channels NS309 (10 -9 -10 -5 M) (Vehicle: 30.5 ± 6.8; TPPU: 55.9 ± 5.2; p=0.028). Interestingly, in female SHRSP, TPPU also improved HPA dilation in response to NS309 (Vehicle: 34.5 ± 4.2; TPPU: 59.0 ± 7.5; p=0.045) but not from GSK1016790A (Vehicle: 59.6± 3.4; TPPU: 64.2 ± 5.1; p=0.99). TPPU enhanced cerebral perfusion in males (Vehicle: 209.8 ± 3.4; TPPU: 227.4 ± 6.5; p=0.035), but not females (Vehicle: 300.1 ± 13.8; TPPU: 302.5 ± 10.8; p=0.89). TPPU improved memory function in female SHRSP (Vehicle: 42.3 ± 5.8; TPPU: 64.4 ± 6.3 %time spent exploring novel object; p=0.02). TPPU treated males had a modest improvement in memory function (Vehicle: 42.3 ± 8.5; TPPU: 61.7 ± 6.1 %time spent exploring novel object; p=0.088). These data suggest that sEH inhibition could be a promising treatment for hypertension-associated cognitive impairment, however the mechanism of this impairment differs between the sexes. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.