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EETs regulate blood vessel formation or angiogenesis
Vascular Pharmacology of Epoxyeicosatrienoic Acids
Abstract
Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid that are produced by the vascular endothelium in responses to various stimuli such as the agonists acetylcholine (ACH) or bradykinin or by shear stress which activates phospholipase A2 to release arachidonic acid. EETs are important regulators of vascular tone and homeostasis. In the modulation of vascular tone, EETs function as endothelium-derived hyperpolarizing factors (EDHFs). In models of vascular inflammation, EETs attenuate inflammatory signaling pathways in both the endothelium and vascular smooth muscle. Likewise, EETs regulate blood vessel formation or angiogenesis by mechanisms that are still not completely understood. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs) and this metabolism limits many of the biological actions of EETs. The recent development of inhibitors of sEH provides an emerging target for pharmacological manipulation of EETs. Additionally, EETs may initiate their biologic effects by interacting with a cell surface protein that is a G-protein coupled receptor (GPCR). Since GPCRs represent a common target of most drugs, further characterization of the EET receptor and synthesis of specific EET agonists and antagonist can be used to exploit many of the beneficial effects of EETs in vascular diseases, such as hypertension and atherosclerosis. This review will focus on the current understanding of the contribution of EETs to the regulation of vascular tone, inflammation and angiogenesis. Furthermore, the therapeutic potential of targeting the EET pathway in vascular disease will be highlighted.
Keywords: epoxyeicosatrienoic acid, cytochrome P450, endothelial cell, hyperpolarization, angiogenesis, inflammation
1. Introduction
Epoxyeicosatrienoic acids (EETs) play a pivotal role in numerous cellular processes involved in vascular function, including vasodilation and inflammation. The multifunctional nature of EETs underlies the importance of these compounds in cardiovascular disease. This review will focus on the current understanding of the contribution of EETs to the regulation of vascular tone, inflammation and angiogenesis. Furthermore, the therapeutic potential of targeting the EET pathway in vascular disease will be highlighted.
2. Biochemistry
In endothelial cells, arachidonic acid is metabolized by the cyclooxygenase (COX), lipoxygenase and cytochrome P450 (CYP) epoxygenase pathways (Rosolowsky and Campbell, 1993, 1996). The epoxygenase pathway leads to the formation of four regioisomeric EETs, 14,15-EET, 11,12-EET, 8,9-EET and 5,6-EET (Figure 1) (Capdevila et al., 1981; Zeldin, 2001). The EETs are released by endothelial cells in response to receptor agonists such as ACH or bradykinin to function as autocrine and paracrine hormones (Campbell et al., 1996a; Fisslthaler et al., 2001; Gauthier et al., 2005; Huang et al., 2005; Nithipatikom et al., 2000). The relative abundance of each EET regioisomer differs among vascular beds depending on which CYP isoforms are expressed, as each CYP isoform generates its own unique profile of EET regioisomers. While many CYP isozymes have been identified in blood vessels, endothelial CYP2C8/2C9 and CYP2J2 function in humans to produce mainly 14,15-EET, with lesser amounts of 11,12-EET (Wu et al., 1996; Zeldin, 2001; Zeldin et al., 1995). No EET production is detected in smooth muscle (Campbell et al., 2006).
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