Polyunsaturated fatty acid (PUFA) metabolites generated by the sequential action of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) enzymes are important modulators of vascular function and integrity. Given the reported role of the sEH in regulating vascular stability in the retina, this study aimed to explore the effects of the PUFA metabolites generated by CYP/sEH on pericyte-endothelial cell junctions and to characterize the effects of sEH related PUFAs on vessel in the diabetic heart.

A comparison of wild-type mice and animals with type1 diabetes (Ins2Akita mice), revealed higher cardiomyocyte expression of the sEH in the diabetic group. The diabetic mice also displayed characteristics of heart failure with preserved ejection fraction (HFpEF) at the age of 6 months, and developed heart failure with reduced ejection fraction (HFrEF) by 12 months. Immunohistochemistry revealed a significant increase in left ventricular capillary density in 12-month-old Ins2Akita mice versus their non-diabetic littermates. However, pericyte coverage was markedly reduced in the diabetic mice. Consistent with the change in sEH expression, fatty acid profiling of the left ventricle reveled increased levels of sEH-derived PUFA diols, e.g. 12,13-dihydroxy-octadecenoic acid (12,13-DiHOME) and 14,15-dihydroxyeicosatrienoic acid (14,15-DHET) in the diabetic group. In vitro studies with 12,13-DiHOME revealed that it targeted endothelial cell-endothelial cell interactions to disrupt barrier function and increase permeability. Similarly, 12,13-DiHOME disrupted pericyte–endothelial cell junctions, and induce on pericyte migration.