Endothelium-derived hyperpolarizing factor and vascular function

Abstract

Endothelial function refers to a multitude of physiological processes that maintain healthy homeostasis of the vascular wall. Exposure of the endothelium to cardiac risk factors results in endothelial dysfunction and is associated with an alteration in the balance of vasoactive substances produced by endothelial cells. These include a reduction in nitric oxide (NO), an increase in generation of potential vasoconstrictor substances and a potential compensatory increase in other mediators of vasodilation. The latter has been surmised from data demonstrating persistent endothelium-dependent vasodilatation despite complete inhibition of NO and prostaglandins. This remaining non-NO, non-prostaglandin mediated endothelium-dependent vasodilator response has been attributed to endothelium-derived hyperpolarizing factor/s (EDHF). Endothelial hyperpolarization is likely due to several factors that appear to be site and species specific. Experimental studies suggest that the contribution of the EDHFs increase as the vessel size decreases, with a predominance of EDHF activity in the resistance vessels, and a compensatory up-regulation of hyperpolarization in states characterized by reduced NO availability. Since endothelial dysfunction is a precursor for atherosclerosis development and its magnitude is a reflection of future risk, then the mechanisms underlying endothelial dysfunction need to be fully understood, so that adequate therapeutic interventions can be designed.

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 (K_Ca ⁺) 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 K_Ca ⁺ channels to cause hyperpolarization and release of K⁺ ions into the subendothelial space. The increase in potassium in the interstitium may activate K_Ca ⁺ channels, inwardly rectifying potassium channels (K_IR ⁺), 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 K_Ca ⁺  channels or by gap junctions. Adenylyl cyclase: AC; cyclic Adenosine monophosphate: cAMP; cyclic guanosine monophosphate: cGMP; soluble guanylyl cyclase: sGC; prostacyclin receptor, IP.