Failure of cerebral arteries to regulate oxygen and nutrient delivery to the brain parenchyma can be catastrophic. In patients with hypertension, this cerebrovascular insufficiency is largely caused by cerebral small vessel disease (CSVD). Importantly, CSVD has been causally linked to the development and progression of all dementias and is the most common pathology underlying the development of vascular cognitive impairment and dementia. Strong evidence links the development of midlife hypertension to cognitive impairment with aging. We utilized pressure myography to assess the effects of hypertension on the function of cerebral parenchymal arterioles from stroke-prone spontaneously hypertensive rats (SHRSP), a model of essential hypertension and CSVD. Through this, we showed that TRPV4-mediated vasodilation is impaired in cerebral arterioles during hypertension. Follow-up studies using TRPV4 knockout rats and endothelial cell-specific TRPV4 knockout mice directly connected the loss of TRPV4 function to cognitive decline. These studies suggested that improving TRPV4 function could be an effective treatment for VCI/VaD. The extreme hemodynamic effects of global TRPV4 activation preclude the use of small-molecule activators as dementia therapies. Therefore, we sought to harness the effects of endogenous TRPV4 agonists, such as epoxyeicosatrienoic acids (EETs), by inhibiting their metabolism by soluble epoxide hydrolase (sEH). We tested the hypothesis that pharmacological inhibition of sEH with trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl)urea (TPPU) in adult (SHRSP) would restore endothelial function in hippocampal parenchymal arterioles (HPAs) and improve cognition. 20-week-old SHRSP were treated with vehicle (n=4-8) or TPPU (3mg/kg/day, n=4-8) for 8 weeks. HPA function was assessed using pressure myography. Data are presented as means ± SEM. In male SHRSP, TPPU improved endothelium-dependent dilation mediated by the TRPV4 agonist GSK1016790A (Vehicle: 22.2±6.1; TPPU: 70.2±6.5; p=.0019) and the nonselective activator of small- and intermediate-Ca²⁺-activated K⁺ channels (SK_Ca and IK_Ca) NS309 (Vehicle: 30.5±6.8; TPPU: 55.9±5.2; p=.028). In female SHRSP, TPPU improved NS309-mediated dilation (Vehicle: 34.5±4.2; TPPU: 59.0±7.5; p=.045) but not dilation induced by TRPV4 activation (Vehicle: 59.6±3.4; TPPU: 64.2±5.1; p=.99). IK_Ca– and SK_Ca– specific antagonists, TRAM-34 and apamin, respectively, were used to determine the individual ion channel contributions to vasodilation. IK_Ca channels are the major contributor to NS309-mediated dilation in HPAs. TPPU treatment increased IK_Ca-mediated vasodilation in male (Vehicle: 4.7%±19.0k TPPU: 63.8%±5.7: p < .01) and female SHRSP (Vehicle: 31.2%±10.2; TPPU: 76.7%±1.2: p=.04). sEH inhibition did not affect dilation induced by SK_Ca activation in either sex (data not shown). TPPU enhanced cerebral perfusion assessed by laser speckle contrast imaging in males (Vehicle: 209.8±3.4; TPPU: 227.4±6.5; p=.035), but not females (Vehicle: 300.1±13.8; TPPU: 302.5±10.8; p=.89). Novel object testing was used to assess memory function. TPPU improved nonspatial memory in female (Vehicle: 42.3±5.8; TPPU: 64.4±6.3 % novel object exploration; p=.02) and male (Vehicle: 43.3±7.5%; TPPU: 65.1±5.4% % novel object exploration; p=.03) SHRSP. 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.