Oxidized lipid mediators generated by PGHS, LOX, or CYP are of central importance in the normal physiology of the endothelium, with their aberrant generation playing a major role in the pathogenesis of inflammatory vascular disease. In addition, these enzymes generate a small amount of lipid radicals that may propagate nonenzymatic lipid peroxidation, a hallmark of atherosclerotic lesions. Although much is known regarding function and control of these pathways in ECs (especially PGHS and LOX), others, especially the CYP enzymes, are less studied. Studying the biological roles and signaling pathways of CYP in EC is becoming a major focus of research in vascular biology and will undoubtedly lead to a fuller understanding of their roles in both normal homeostasis and vascular pathophysiology.
Finally, although much is known regarding the biological chemistry and cell biology of these pathways, their relative importance in vessels of different origin is not clear. In particular, the role of PGHS, LOX, or CYP in control of vascular tone through regulating vascular function in large vessels, resistance vessels, and capillary beds may vary tremendously. Elucidation of tissue-specific functions and control mechanisms for lipid oxidation pathways in subtypes of EC is becoming an area of active and fruitful investigation that will yield major insights into their role in regulating vascular biology in health and disease.
Lipoxygenases: Lipid oxidizing enzymes that play important roles in vascular function and immune regulation. There are several mammalian isoforms, with one in particular (12/15-lipoxygenase) being involved in vascular dysfunction associated with hypertension, diabetes, and atherogenesis.
Nitric oxide: Free radical signaling molecule generated by oxidation of L-arginine by nitric oxide synthases (NOS), which causes smooth muscle relaxation and inhibits platelet and leukocyte activation.
Prostaglandin H synthases: Lipid oxidizing enzymes that generate prostaglandins, signaling mediators that regulate vessel tone (e.g., prosta-cyclin) and platelet aggregation (e.g., thromboxane).
Research funding from the Wellcome Trust and British Heart Foundation is gratefully acknowledged.
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Drs. Anning and O'Donnell are based at Cardiff University, UK. Their work focuses on lipoxygenase and nitric oxide signaling in the vasculature and is funded by the British Heart Foundation and Wellcome Trust.
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