Arachidonic acid cascade in endothelial pathobiology

doi:10.1016/j.mvr.2005.01.007

Microvascular Research

Volume 69, Issue 3, May 2005, Pages 107-127

https://doi.org/10.1016/j.mvr.2005.01.007 Get rights and content

Abstract

Arachidonic acid (AA) and its metabolites (eicosanoids) represent powerful mediators, used by organisms to induce and suppress inflammation as a part of the innate response to disturbances. Several cell types participate in the synthesis and release of AA metabolites, while many cell types represent the targets for eicosanoid action. Endothelial cells (EC), forming a semi-permeable barrier between the interior space of blood vessels and underlying tissues, are of particular importance for the development of inflammation, since endothelium controls such diverse processes as vascular tone, homeostasis, adhesion of platelets and leukocytes to the vascular wall, and permeability of the vascular wall for cells and fluids. Proliferation and migration of endothelial cells contribute significantly to new vessel development (angiogenesis). This review discusses endothelial-specific synthesis and action of arachidonic acid derivatives with a particular focus on the mechanisms of signal transduction and associated intracellular protein targets.

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).

References (234)

F. Antohe et al.
Heart microvessels and aortic endothelial cells express the 15 kDa heart-type fatty acid-binding proteins
Eur. J. Cell Biol.
(1998)
C. Antoine et al.
Time-dependent utilization of platelet arachidonic acid by the neutrophil in formation of 5-lipoxygenase products in platelet- neutrophil co-incubations
Biochim. Biophys. Acta
(1992)
A.W. Ashton et al.
Inhibition of endothelial cell migration, intercellular communication, and vascular tube formation by thromboxane A₂
J. Biol. Chem.
(1999)
M.A. Balboa et al.
Novel group V phospholipase A₂ involved in arachidonic acid mobilization in murine P388D1 macrophages
J. Biol. Chem.
(1996)
J. Balsinde et al.
Phospholipase A₂ regulation and arachidonic acid mobilization
FEBS Lett.
(2002)
D. Bishop-Bailey et al.
Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J₂
J. Biol. Chem.
(1999)
M.E. Brezinski et al.
Lipoxins stimulate prostacycline generation by human endothelial cells
FEBS Lett.
(1989)
M.R. Buchanan et al.
Regulation of endothelial cell and platelet receptor-ligand binding by the 12- and 15-lipoxygenase monohydroxides, 12-, 15-HETE and 13-HODE
Prostaglandins, Leukotrienes Essent. Fatty Acids
(1998)
J.H. Capdevila et al.
Biochemical and molecular properties of the cytochrome P450 arachidonic acid monooxygenases
Prostaglandins Other Lipid Mediators
(2002)
E.A. Capper et al.
Mammalian phospholipases A₂: mediators of inflammation, proliferation and apoptosis
Prog. Lipid Res.
(2001)

C.J. Dunn et al.

The role of cyclooxygenase and lipoxygenase pathways in the adhesive interaction between bovine polymorphonuclear leukocytes and bovine endothelial cells

Prostaglandins, Leukotrienes Med.

(1986)

A. Fiorio Pla et al.

Calcium influx, arachidonic acid, and control of endothelial cell proliferation

Cell Calcium

(2001)

I. Fleming

Cytochrome p450 epoxygenases as EDHF synthases

Pharmacol. Res.

(2004)

C.D. Funk et al.

Lipoxygenase genes and their targeted disruption

Prostaglandins Other Lipid Mediators

(2002)

A. Gil

Polyunsaturated fatty acids and inflammatory diseases

Biomed. Pharmacother.

(2002)

K. Gronert et al.

Selectivity of recombinant human leukotriene D4, leukotriene B4, and lipoxin A₄ receptors with aspirin-triggered 15-epi-LXA4 and regulation of vascular and inflammatory responses

Am. J. Pathol.

(2001)

A. Habib et al.

Comparison of leukotriene A₄ metabolism into leukotriene C4 by human platelets and endothelial cells

Arch. Biochem. Biophys.

(1992)

B. Han et al.

Gamma-glutamyl leukotrienase, a novel endothelial membrane protein, is specifically responsible for leukotriene D4 formation in vivo

Am. J. Pathol.

(2002)

D.G. Harrison et al.

Endothelial control of vasomotion and nitric oxide production

Cardiol. Clin.

(2003)

T. Higaki et al.

A role of protein kinase C in the regulation of cytosolic phospholipase A₂ in bradykinin-induced PGI₂ synthesis by human vascular endothelial cells

Microvasc. Res.

(1999)

S. Hu et al.

Activation of K⁺ channel in vascular smooth muscles by cytochrome P450 metabolites of arachidonic acid

Eur. J. Pharmacol.

(1993)

Y. Kanaoka et al.

Attenuated zymosan-induced peritoneal vascular permeability and IgE-dependent passive cutaneous anaphylaxis in mice lacking leukotriene C₄ synthase

J. Biol. Chem.

(2001)

I. Kudo et al.

Phospholypase A₂ enzymes

Prostaglandins Other Lipid Mediators

(2002)

H. Kuhn et al.

Mammalian arachidonate 15-lipoxygenases. Structure, function, and biological implications

Prostaglandins Other Lipid Mediators

(2002)

G. Kunos et al.

The quest for a vascular endothelial cannabinoid receptor

Chem. Phys. Lipids

(2002)

O. Laneuville et al.

Hepoxilin A₃ (HXA₃) is formed by the rat aorta and is metabolized into HxA₃-C, a glutathione conjugate

Biochim. Biophys. Acta

(1991)

Y.W. Lee et al.

Interleukin 4 induces transcription of the 15-lipoxygenase 1 gene in human endothelial cells

J. Lipid Res.

(2001)

P. Akarasereenont et al.

Cytokine-mediated induction of cyclo-oxygenase-2 by activation of tyrosine kinase in bovine endothelial cells stimulated by bacterial lipopolysaccharide

Br. J. Pharmacol.

(1995)

D.F. Alvarez et al.

Role of EETs in regulation of endothelial permeability in rat lung

Am. J. Physiol.: Lung Cell. Mol. Physiol.

(2004)

S.L. Amaral et al.

CYP4A metabolites of arachidonic acid and VEGF are mediators of skeletal muscle angiogenesis

Am. J. Physiol.: Heart Circ. Physiol.

(2003)

S. Antoniotti et al.

Control of endothelial cell proliferation by calcium influx and arachidonic acid metabolism: a pharmacological approach

J. Cell. Physiol.

(2003)

M. Artwohl et al.

Free fatty acids trigger apoptosis and inhibit cell cycle progression in human vascular endothelial cells

FASEB J.

(2004)

M. Aurrand-Lions et al.

Role of interendothelial adhesion molecules in the control of vascular functions

Vasc. Pharmacol.

(2003)

P.J. Barnes et al.

Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases

N. Engl. J. Med.

(1997)

P. Bentzer et al.

Low-dose prostacyclin restores an increased protein permeability after trauma in cat skeletal muscle

J. Trauma

(2004)

H. Bisgaard

Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonist in asthma

Allergy

(2001)

N.V. Bogatcheva et al.

Mitogen-activated protein kinases in endothelial pathophysiology

J. Invest. Med.

(2003)

T. Bombeli et al.

Anticoagulant properties of the vascular endothelium

Thromb. Haemostasis

(1997)

J.V. Bonventre et al.

Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A₂

Nature

(1997)

J.F. Bouchard et al.

Participation of prostaglandin E₂ in the endothelial protective effect of ischaemic preconditioning in isolated rat heart

Cardiovasc. Res.

(2000)

A.R. Brash

Arachidonic acid as a bioactive molecule

J. Clin. Invest.

(2001)

J. Bratt et al.

Mechanism for lipoxin A₄-induced neutrophil-dependent cytotoxicity for human endothelial cells

J. Lab. Clin. Med.

(1995)

R.M. Breyer et al.

Prostanoid receptors: subtypes and signaling

Annu. Rev. Pharmacol. Toxicol.

(2001)

S.I. Briand et al.

Calcium-calmodulin plays a major role in bradykinin-induced arachidonic acid release by bovine aortic endothelial cells

J. Cell. Biochem.

(1996)

C. Brink et al.

International union of pharmacology: XXXVII. Nomenclature for leukotriene and lipoxin receptors

Pharmacol. Rev.

(2003)

W.W. Busse

Leukotrienes and inflammation

Am. J. Respir. Crit. Care Med.

(1998)

P.C. Calder et al.

Polyunsaturated fatty acids, inflammation and immunity

Eur. J. Clin. Nutr.

(2002)

D.S. Calnek et al.

Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells

Arterioscler., Thromb., Vasc. Biol.

(2003)

W.B. Campbell et al.

Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors

Circ. Res.

(1996)

S. Chakraborti et al.

Oxidant-mediated activation of phospholipase A₂ in pulmonary endothelium

Am. J. Physiol.

(1989)

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Arachidonic acid cascade in endothelial pathobiology

Abstract

Section snippets

Review outline

Endothelial functions

Arachidonic acid release, uptake, conversion, and action in EC

Cyclooxygenase metabolites of AA

Lipoxygenase metabolites of AA

Monooxygenase metabolites of AA

Summary

Acknowledgments

Eur. J. Cell Biol.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

FEBS Lett.

Prostaglandins, Leukotrienes Essent. Fatty Acids

Prostaglandins Other Lipid Mediators

Prog. Lipid Res.

Prostaglandins, Leukotrienes Med.

Cell Calcium

Pharmacol. Res.

Prostaglandins Other Lipid Mediators

Biomed. Pharmacother.

Am. J. Pathol.

Arch. Biochem. Biophys.

Am. J. Pathol.

Cardiol. Clin.

Microvasc. Res.

Eur. J. Pharmacol.

J. Biol. Chem.

Prostaglandins Other Lipid Mediators

Prostaglandins Other Lipid Mediators

Chem. Phys. Lipids

Biochim. Biophys. Acta

J. Lipid Res.

Cytokine-mediated induction of cyclo-oxygenase-2 by activation of tyrosine kinase in bovine endothelial cells stimulated by bacterial lipopolysaccharide

Br. J. Pharmacol.

Role of EETs in regulation of endothelial permeability in rat lung

Am. J. Physiol.: Lung Cell. Mol. Physiol.

CYP4A metabolites of arachidonic acid and VEGF are mediators of skeletal muscle angiogenesis

Am. J. Physiol.: Heart Circ. Physiol.

Control of endothelial cell proliferation by calcium influx and arachidonic acid metabolism: a pharmacological approach

J. Cell. Physiol.

Free fatty acids trigger apoptosis and inhibit cell cycle progression in human vascular endothelial cells

FASEB J.

Role of interendothelial adhesion molecules in the control of vascular functions

Vasc. Pharmacol.

Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases

N. Engl. J. Med.

Low-dose prostacyclin restores an increased protein permeability after trauma in cat skeletal muscle

J. Trauma

Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonist in asthma

Allergy

Mitogen-activated protein kinases in endothelial pathophysiology

J. Invest. Med.

Anticoagulant properties of the vascular endothelium

Thromb. Haemostasis

Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2

Nature

Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart

Cardiovasc. Res.

Arachidonic acid as a bioactive molecule

J. Clin. Invest.

Mechanism for lipoxin A4-induced neutrophil-dependent cytotoxicity for human endothelial cells

J. Lab. Clin. Med.

Prostanoid receptors: subtypes and signaling

Annu. Rev. Pharmacol. Toxicol.

Calcium-calmodulin plays a major role in bradykinin-induced arachidonic acid release by bovine aortic endothelial cells

J. Cell. Biochem.

International union of pharmacology: XXXVII. Nomenclature for leukotriene and lipoxin receptors

Pharmacol. Rev.

Leukotrienes and inflammation

Am. J. Respir. Crit. Care Med.

Polyunsaturated fatty acids, inflammation and immunity

Eur. J. Clin. Nutr.

Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells

Arterioscler., Thromb., Vasc. Biol.

Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A₂

Participation of prostaglandin E₂ in the endothelial protective effect of ischaemic preconditioning in isolated rat heart

Mechanism for lipoxin A₄-induced neutrophil-dependent cytotoxicity for human endothelial cells

Oxidant-mediated activation of phospholipase A₂ in pulmonary endothelium