Welcome to the Institute for Vascular Signalling

Lipid Mediators

Fatty acids are important components of the human body. Apart from their role as constituents of cellular membranes, polyunsaturated fatty acids (PUFAs) can be enzymatically processed to generate a wide range of bioactive lipid mediators that regulate numerous biological processes to influence physiology as well as pathophysiology. Much of our work is focused on the cytochrome P450 (CYP) /soluble epoxide hydrolase (sEH) pathway and the role of the PUFA-derived mediators generated in vascular homeostasis. We have a keen interest in the identification of novel lipid mediators belonging to this pathway in inflammation, angiogenesis, cell-cell interactions and the maintenance of vascular integrity. The metabolic syndrome and diabetes are associated with changes in CYP and sEH expression as well as PUFA metabolism, so many or our projects focus on the assessing the role of PUFA-derived lipid mediators in the associated cardiovascular complications e.g., diabetic retinopathy and heart failure.

The role of 19,20-DHDP in physiological retinal angiogenesis and retinopathy. (A) Physiological (sprouting) angiogenesis. In the retina, the end feet of Müller glial cells are in close contact with the developing vasculature. This means that the 19,20-DHDP generated by Müller cells (and to a lesser extent by astrocytes) can affect the endothelial cell phenotype. By targeting PS1 and inhibiting the γ-secretase 19,20-DHDP interferes with Notch signaling and thus the tip versus stalk cell specification of retinal endothelial cells at the angiogenic front. (B) Diabetic retinopathy. Diabetes increases the expression of the sEH in Müller cells, which results in a marked increase in 19,20-DHDP. The high concentrations of 19,20-DHDP target cholesterol binding proteins such as PS1, VE-cadherin, and N-cadherin to dissolve endothelial cell-pericyte contacts. This contributes to the loss of mural cells or pericyte “drop-off.” The simultaneous disruption of endothelial cell-endothelial cell junctions results in increased vascular permeability and loss of barrier function. sEH inhibition effectively prevents the generation of 19,20-DHDP and prevents the development of non-proliferative diabetic retinopathy in a mouse model of type 1 diabetes.
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