The Gatekeepers in the Mouse Ophthalmic Artery: Endothelium-Dependent Mechanisms of Cholinergic Vasodilation

Abstract

Cholinergic regulation of arterial luminal diameter involves intricate network of intercellular communication between the endothelial and smooth muscle cells that is highly dependent on the molecular mediators released by the endothelium. Albeit the well-recognized contribution of nitric oxide (NO) towards vasodilation, the identity of compensatory mechanisms that maintain vasomotor tone when NO synthesis is deranged remain largely unknown in the ophthalmic artery. This is the first study to identify the vasodilatory signalling mechanisms of the ophthalmic artery employing wild type mice. Acetylcholine (ACh)-induced vasodilation was only partially attenuated when NO synthesis was inhibited. Intriguingly, the combined blocking of cytochrome P450 oxygenase (CYP450) and lipoxygenase (LOX), as well as CYP450 and gap junctions, abolished vasodilation; demonstrating that the key compensatory mechanisms comprise arachidonic acid metabolites which, work in concert with gap junctions for downstream signal transmission. Furthermore, the voltage-gated potassium ion channel, Kv1.6, was functionally relevant in mediating vasodilation. Its localization was found exclusively in the smooth muscle. In conclusion, ACh-induced vasodilation of mouse ophthalmic artery is mediated in part by NO and predominantly via arachidonic acid metabolites, with active involvement of gap junctions. Particularly, the Kv1.6 channel represents an attractive therapeutic target in ophthalmopathologies when NO synthesis is compromised.

Angiotensin II Induces Oxidative Stress and Endothelial Dysfunction in Mouse Ophthalmic Arteries via Involvement of AT1 Receptors and NOX2

“…The EDHF portion was mediated by CYP450 and 12/15-LOX metabolites. These findings are in agreement with previous observations in freshly isolated C57BL/6J mouse ophthalmic arteries, suggesting that overnight incubation of vessels had no marked effect on the contribution of endothelial signaling pathways to vasodilation [41].…”

“…After preconstriction, responses to the endothelium-independent nitric oxide (NO) donor, sodium nitroprusside (SNP, 10 −9 M to 10 −4 M, Sigma-Aldrich) and to the endothelium-dependent vasodilator, acetylcholine (10 −9 M to 10 −4 M; Sigma-Aldrich) were measured. We previously demonstrated in ophthalmic arteries from mice of different genetic backgrounds, including C57BL/6J mice, that acetylcholine induces only significant vasodilation when the endothelium is intact [ 40 , 41 , 42 ]. Between each concentration–response curve, the perfusion system was washed with Krebs buffer.…”

Chronic Intermittent Hypoxia Alters Rat Ophthalmic Artery Reactivity Through Oxidative Stress, Endothelin and Endothelium-Derived Hyperpolarizing Pathways

“…In particular, the contribution of gap junctions and voltage-gated potassium channels should be explored in view of recent data in mouse OA. 43 Finally, we have shown that ET R A, ET R B, eNOS, and nNOS genes were significantly upregulated in rat optic nerve after a 14-day exposure to IH. Interestingly, this was not observed in the retina, supporting the idea that regulation of these genes is tissue-dependent, as previously shown in carotid, 44 pulmonary, 45 and brain 46 arteries.…”

Interference with AGEs formation and AGEs-induced vascular injury mediates curcumin vascular protection in metabolic syndrome

“…It is possible, therefore, that a favorable effect for CUR could be only seen when a prophylactic regimen is assumed. It should also be considered that the vasodilatory response elicited by ACh is multifactorial, involving both NO-dependent and independent cellular pathways 39,40 . A differential interaction of CUR with these cellular events might possibly explain its little or no capacity in combating the reduced Ach vasodilations in MetS aortas.…”