Epoxyeicosatrienoic acids and endothelium-dependent responses

Abstract

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid that are produced by the vascular endothelium in response to agonists such as bradykinin and acetylcholine or physical stimuli such as shear stress or cyclic stretch. In the vasculature, the EETs have biological actions that are involved in the regulation of vascular tone, hemostasis, and inflammation. In preconstricted arteries in vitro, EETs activate calcium-activated potassium channels on vascular smooth muscle and the endothelium causing membrane hyperpolarization and relaxation. These effects are observed in a variety of arteries from experimental animals and humans; however, this is not a universal finding in all arteries. The mechanism of EET action may vary. In some arteries, EETs are released from the endothelium and are transferred to the smooth muscle where they cause potassium channel activation, hyperpolarization, and relaxation through a guanine nucleotide binding protein-coupled mechanism or transient receptor potential (TRP) channel activation. In other arteries, EETs activate TRP channels on the endothelium to cause endothelial hyperpolarization that is transferred to the smooth muscle by gap junctions or potassium ion. Some arteries use a combination of mechanisms. Acetylcholine and bradykinin increase blood flow in dogs and humans that is inhibited by potassium channel blockers and cytochrome P450 inhibitors. Thus, the EETs are endothelium-derived hyperpolarizing factors mediating a portion of the relaxations to acetylcholine, bradykinin, shear stress, and cyclic stretch and regulate vascular tone in vitro and in vivo.

Fig 1

Chemical structures of epoxyeicosatrienoic acid (EET) agonists and EET antagonists. (epoxyeicosa-5Z-enoic acid=EE5ZE; epoxyeicosa-8Z-enoic acid=EE8ZE; mSI=methylsulfonylimide)

Fig 2

Pathway of EET synthesis and action in the vascular wall. EETs may function as an EDHF by two possible mechanisms: (A) EETs act as transferrable factors released from the endothelium and acting on smooth muscle cells to cause activation of the large conductance, calcium (Ca)-sensitive potassium (K_Ca) channels. This leads to K efflux, an increase in the membrane potential (Em) or hyperpolarization and relaxation. (B) EETs act in an autocrine manner on endothelial cells to promote Ca influx through TRPV4 or TRPC3 and TRPC6 channels. Calcium activates small conductance (SK) and intermediate conductance (IK) K_Ca channels to cause hyperpolarization and release of K ions into the sub-endothelial space. Potassium ions stimulate the sodium-potassium ATPase or inward rectifying (K_ir) K channel. The endothelial hyperpolarization and K ion mediate hyperpolarization and relaxation of vascular smooth muscle. Gap junctions provide electrical coupling between endothelial cells and smooth muscle cells

Fig 3

Biological effects of exogenous EETs. Effects of EETs are listed on a concentration-response line. Threshold concentrations for the activity are indicated

Fig 4

Pathway of EET synthesis and action in the vascular wall. EETs may hyperpolarize and relax vascular smooth muscle by two additional mechanisms: (A) EETs are released by the endothelium and activate TRPV4 channels on smooth muscle cells. The calcium (Ca) influx through TRPV4 channels promotes Ca sparks from the endoplasmic reticulum activating large conductance, Ca-activated K (BK_Ca) channels. This promotes K efflux, an increase in the membrane potential (Em) or hyperpolarization and relaxation. (B) EETs are released by the endothelium and stimulate cyclic AMP production through activation of adenylyl cyclase by the guanine nucleotide binding protein Gαs. Protein kinase (PKA) is activated by cyclic AMP leading to phosphorylation and activation of ATP-sensitive potassium channels. This promotes hyperpolarization and relaxation