Molecular regulation of endothelial and vascular dysfunction by lipid lactone mediators

Microvascular dysfunction is an established risk factor for developing cardiometabolic diseases like hypertension, diabetes, and also dementia. Under these conditions, excessive oxidative stress reduces nitric oxide (NO) bioavailability and NO-mediated vascular dilation. In the microvessels, endothelial-derived hyperpolarizing factors (EDHFs) may compensate for the loss of NO-mediated dilation. Recently we showed that lactone oxylipins generated from the polyunsaturated fatty acids (PUFA-Ls) CYP450 epoxygenase pathway are potential new EDHFs. Unlike known epoxy-EDHFs, the PUFA-Ls structure is chemically stable and is a poor substrate for the epoxide hydrolase enzyme. However, the PUFA-L role in the microvessels dilation is unknown. Our study aimed to reveal their potential mechanism and physiological function in microvascular dilation.

In human microvessels extracted from hypertensive patients, PUFA-Ls induced dilation in an endothelial-dependent mechanism that does not involve NO. In a hypertensive rat model, PUFA-Ls reduced blood pressure in vivo, resulting from the recovery of the microvascular dilation capacity. The mechanism of action was revealed in human endothelial cells, where PUFA-Ls initiated a dose-dependently calcium increase which further activates calcium-dependent potassium efflux and hyperpolarization. Using ion fluxes and electrophysiological measurements with pharmacological antagonists, we found that the PUFA-Ls are potential ligands for G-protein coupled receptors that activate the PLC-IP3 pathway and mediate calcium flux from the endoplasmic reticulum. In addition, gene expression analysis performed using single-cell RNA sequencing for mesenteric arteries extracted after PUFA-Ls treatment revealed a potential involvement of mesenchymal cells.

Thus, we conclude that PUFA-derived lactones are novel EDHFs and are potential microvascular dilation and healing regulators.