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Regulation of endothelial cell functions by basement membrane‐ and arachidonic acid‐derived products

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Abstract Angiogenesis, the formation of new blood vessels from preexisting vasculature, is required for normal physiological as well as pathological events. The angiogenic process requires endothelial cells to proliferate, migrate, and undergo tubulogenesis. These multistep processes necessitate secretion of pro‐angiogenic growth factors, activation of specific intracellular signaling, and interaction of endothelial cells with basement membrane (BM) extracellular matrix components. The generation and release of angiogenic molecules are highly regulated and are influenced by numerous factors, including BM‐derived fragments, proteolytic enzymes, as well as metabolites of arachidonic acid (AA). The interactions between these key modulators of angiogenesis is extremely complex, as AA metabolites can regulate the synthesis of soluble angiogenic factors, BM components, as well as enzymes capable of cleaving BM components, which result in the generation of pro‐ and/or anti‐angiogenic products. Furthermore, some BM‐derived fragments can alter the expression of AA‐converting enzymes and consequently the synthesis of angiogenic factors. In this review we describe the relationship between BM components and AA metabolites with respect to the regulation of endothelial cell functions in health and disease. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Models of Systems Properties and Processes > Cellular Models Developmental Biology > Developmental Processes in Health and Disease Laboratory Methods and Technologies > Macromolecular Interactions, Methods Biological Mechanisms > Regulatory Biology

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Potential cross‐talk between basement membrane components and arachidonic acid metabolizing enzymes. Endothelial cell derived cyclooxygenases, lipoxygenases, and cytochrome p450 monooxygenases stimulate angiogenesis by promoting the synthesis of soluble growth factors (a); basement membrane components (b); and/or matrix degrading enzymes (c). In turn, these degrading enzymes can generate basement membrane‐derived fragments capable of regulating the expression of arachidonic acid‐metabolizing enzymes (d).

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Schematic representation of epoxyeicosatrienoic and hydroxyeicosatetraenoic acid synthesis and functions. (a) Arachinodic acid (AA) can be converted by (1) the cytochrome P450 epoxygenases (CYP2C isoforms) to four different epoxyeicosatrienoic acids (5,6 −9–11, 12‐ and 14,15‐EET); or (2) the cytochrome P450 ω ‐hydroxylases (CYP4A isoforms) to two different hydroxyeicosatetraenoic acid (19‐ and 20‐HETE). (b) EETs and HETEs can be generated endogenously by endothelial cells and can control different endothelial cell functions.

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Schematic representation of lipoxogyenase‐derived hydroxyeicosatetraenoic acid and their functions. (a) Arachinodic acid (AA) is converted by mammalian lipoxygenases (LOXs) to four major hydroxyeicosatetraenoic acid (5‐, 8‐, 12‐, and 15‐HETE). (b) Effect of 12‐ and 15‐HETEs on endothelial cell (EC) functions.

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Schematic representation of prostanoid synthesis and functions. (a) Arachinodic acid (AA) is converted by cyclooxygenases (COXs) to PGH2. This intermediate is then converted to thromboxane (TxA2) by the thromboxane synthase (TXs); to prostacyclins (PGI2) by the prostacyclin synthase (PGIS); to PGD2 by the prostaglandin D synthases (PGDS); to PGF by the prostaglandin F synthase (PGFS); and to PGE2 by the prostaglandin E synthase (PGS). (b) PGE2 can activate four different G protein coupled receptors (EP1–4), thus controlling different endothelial cell (EC) functions.

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Laboratory Methods and Technologies > Macromolecular Interactions, Methods
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Models of Systems Properties and Processes > Cellular Models
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