Endothelium-Derived Hyperpolarizing Factor and Vascular Function
Figure 1
Mechanisms for endothelial cell mediated relaxation. Agonist (bradykinin/acetylcholine/substance P) or shear stress increases the activity of endothelial NO synthase (eNOS) and cyclooxygenase (COX), providing nitric oxide x(NO) and prostacyclin(PGI2)-mediated dilation. There are multiple potential EDHF pathways. Increases in intracellular calcium activates phospholipase A2 (PLC) to produce arachidonic acid. Its metabolism by cytochrome P450 2C (CYP4502c) generates eicosatrienoic acids (EETs) that can stimulate calcium dependent potassium channels in endothelial and smooth muscle cells. EETs may also directly activate gap junctions (Gap). EETs may also act in an autocrine manner on endothelial cells by activating transient receptor potential (TRP) V4 channels, which promote Calcium (Ca++) influx further increasing the calcium concentration and activating channels to cause hyperpolarization and release of K+ ions into the subendothelial space. The increase in potassium in the interstitium may activate channels, inwardly rectifying potassium channels , or the Na+-K+ pump on smooth muscle cells and cause hyperpolarization. Smooth muscle hyperpolarization in turn results in relaxation by closing voltage-gated channels leading to a fall in Ca++ concentration and subsequent vasodilation. The action of eNOS (with cofactor tetrahydrobiopterin [BH4]) and oxidases on oxygen (O2) produces the reactive oxygen species superoxide (.O2−). Hydrogen peroxide (H2O2) generated by dismutation of superoxide anions by superoxide dismutase (SOD) can also cause hyperpolarization by activating endothelial and smooth muscle channels or by gap junctions. Adenylyl cyclase: AC; cyclic Adenosine monophosphate: cAMP; cyclic guanosine monophosphate: cGMP; soluble guanylyl cyclase: sGC; prostacyclin receptor, IP.
