Abstract

AbstractThe concept of Endothelium Derived Relaxing Factor (EDRF), put forward by Furchgott in the earlier 80s of the past century, implies that nitric oxide (NO) produced by NO synthase (NOS) in the endothelium in response to acetylcholine (ACh) passively diffuses to the underlying vascular smooth muscle cells (VSMC) thereby reducing vascular tension. It was thought that VSMC do not express NOS by themselves, but to the time of those studies immunohistochemical techniques were not what they are now. State-of-the-art immunohistochemistry permits nowadays to localize NOS both to the endothelium and to VSMC. However, the principal question remained unanswered, is the NO generation by VSMC physiologically relevant? We hypothesized that the destruction of the vascular wall anatomical integrity by rubbing the blood vessel intimal surface may increase vascular superoxides that, in turn, reduce NO bioactivity. To address this issue, we examined ACh-induced vasorelaxation in endothelium-deprived blood vessels under protection against oxidative stress and found that superoxide scavengers - tempol and N-acetyl-L-cysteine - restored vasodilatory responses to ACh in endothelium-deprived blood vessels without influencing the vascular wall tension in intact blood vessels. Herewith we provided the first evidence that VSMC can release NO in amounts sufficient to account for the vasorelaxatory response to ACh. In contrast to the commonly accepted concept of the obligatory role of endothelial cells in the relaxation of arterial smooth muscle, the local NO generation by VSMC can modulate vascular functions in an endothelium-independent manner.

Highlights

  • (later termed Endothelium Derived Relaxing Factor (EDRF) for endothelium-derived relaxing factor) that acted on the subjacent vascular smooth muscle cells (VSMC) to produce relaxation, whereby VSMC were regarded as passive recipients of nitric oxide (NO) from endothelial cells

  • The principal question remained unanswered, is the NO generation by VSMC physiologically relevant? We hypothesized that the destruction of the vascular wall anatomical integrity by rubbing the blood vessel intimal surface may increase vascular superoxides that, in turn, reduce NO bioactivity

  • We provided the first evidence that VSMC can release NO in amounts sufficient to account for the vasorelaxatory response to ACh

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Summary

Introduction

(later termed EDRF for endothelium-derived relaxing factor) that acted on the subjacent VSMC to produce relaxation, whereby VSMC were regarded as passive recipients of NO from endothelial cells. Aspects of the anatomical integrity of the organ (i.e., blood vessel) subjected to experiments with rubbing the blood vessel intimal surface were neglected More recently it was, found that the destruction of the vascular wall integrity in the process of endothelial denudation destroys myoendothelial gap junctional communications in VSMC5 and impairs K+-induced vasorelaxation (background-K+ channel activation)[6]. The objective of the present study was to elucidate the role of superoxides associated with vascular dysfunction induced by destroying the anatomical integrity of the blood vessel In these experiments, thoracic aorta rings, mesenteric artery rings and pulmonary artery rings from intact and denudated blood vessels of rat were first subjected to morphological and immunohistochemical control to confirm the absence of the endothelial layer in endothelium-deprived blood vessels and to demonstrate NOS expression in blood vessels under study. Tempol (3x10-3 M), a superoxide dismutase mimetic, reversed the ACh-mediated relaxations in endothelium-deprived aortic ring preparations with the maximum relaxation of 34.58 ± 6.65% (p

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