Arachidonic acid cascade in endothelial pathobiology
Section snippets
Review outline
This review is focused on the role of endothelium in eicosanoid-induced alteration of vascular function. Two aspects will be selectively examined here, namely, (a) the contribution of endothelium to eicosanoid generation and (b) endothelial-specific action of eicosanoids. In the first section, the review will provide background information about endothelial functions and the major signaling pathways that control them. The next section will analyze the mechanisms of AA release, uptake, and
Endothelial functions
The endothelium represents a multifunctional organ with several activities vital for the vascular system. Under normal conditions, endothelial cells (EC) form a monolayer, which restricts the flow of luminal contents into surrounding tissue spaces (Fig. 2). Endothelial barrier dysfunction occurs when agonist stimulation produces cellular contraction, disruption of cell–cell contacts, and subsequent intercellular gap formation (Dudek and Garcia, 2001). The actin cytoskeleton is critical for
Arachidonic acid release, uptake, conversion, and action in EC
The primary pathway leading to AA formation in the cell is the hydrolysis of phospholipids by phospholipase A2 (PLA2). This reaction also generates other inflammatory mediators, namely lysophosholipids, which include the precursor of platelet-activating factor PAF (reviewed in (Balsinde et al., 2002, Capper and Marshall, 2001, Kudo and Murakami, 2002)). As an alternative, arachidonate can be generated through a set of reactions initiated by phospholipases C and D (PLC and PLD, respectively) (
Cyclooxygenase metabolites of AA
The products of the first branch of AA oxygenation, prostanoids (prostaglandins and thromboxanes), regulate numerous pathological and physiological functions, including inflammation development and resolution, and angiogenesis (Morita, 2002). Prostanoid synthesis requires conversion of AA to prostaglandin G2 and H2 by prostaglandin G2/H2 synthases (usually named cyclooxygenases (COX1, COX2, COX3)), located in the endoplasmic reticulum or nuclear envelope (Fitzgerald, 2003, Morita, 2002, Smith
Lipoxygenase metabolites of AA
Similar to COX products, lipoxygenized AA metabolites play important roles in inflammation development and resolution, and, to some extent, may be involved in vascular remodeling. To initiate the production of diverse lipoxygenized products (leukotrienes (LT), HETEs, lipoxins (LX), and hepoxilins), group of enzymes called lipoxygenases (LOX) (Fig. 3) stereospecifically incorporate molecular oxygen into different position of the AA chain. LOX nomenclature corresponds to the oxygenated carbonyl
Monooxygenase metabolites of AA
Monooxygenized products of AA conversion were initially characterized by their vasoactivity and potential roles in the pathophysiology of experimental hypertension, angiogenesis, and inflammation development (Capdevila and Falck, 2002, Fleming, 2004). Monooxygenized products, namely epoxy- and hydroxy-metabolites of AA (EETs and HETEs), are produced by cytochrome P450 monooxygenases (CYP), the multifunctional enzymes that participate in the conversion of cholesterol, steroids, bile acids,
Summary
Increased AA release and conversion to bioactive metabolites are an evolutionary-based response of living organisms to tissue disturbances by various stimuli. The endothelium participates in such responses, acting as a source and a target for AA metabolites. Thus, along with mobile inflammatory cells, the endothelium regulates the intensity and duration of inflammatory and immune responses. Multidirectional and often opposing action of numerous AA products on barrier function, angiogenesis, and
Acknowledgments
This work was supported by grants from National Heart, Lung, and Blood Institutes (HL67307, HL68062, and HL58064).
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