Hypoxic Conditions Promote Rhythmic Contractile Oscillations Mediated by Voltage-Gated Sodium Channels Activation in Human Arteries.

Anne Virsolvy,Sylvain Richard,Azzouz Charrabi,Aurélie Fort,Franck Aimond,Maurice Hayot,Lucie Erceau

doi:10.3390/ijms22052570

Abstract

Arterial smooth muscle exhibits rhythmic oscillatory contractions called vasomotion and believed to be a protective mechanism against tissue hypoperfusion or hypoxia. Oscillations of vascular tone depend on voltage and follow oscillations of the membrane potential. Voltage-gated sodium channels (Nav), responsible for the initiation and propagation of action potentials in excitable cells, have also been evidenced both in animal and human vascular smooth muscle cells (SMCs). For example, they contribute to arterial contraction in rats, but their physiopathological relevance has not been established in human vessels. In the present study, we investigated the functional role of Nav in the human artery. Experiments were performed on human uterine arteries obtained after hysterectomy and on SMCs dissociated from these arteries. In SMCs, we recorded a tetrodotoxin (TTX)-sensitive and fast inactivating voltage-dependent INa current. Various Nav genes, encoding α-subunit isoforms sensitive (Nav 1.2; 1.3; 1.7) and resistant (Nav 1.5) to TTX, were detected both in arterial tissue and in SMCs. Nav channels immunostaining showed uniform distribution in SMCs and endothelial cells. On arterial tissue, we recorded variations of isometric tension, ex vivo, in response to various agonists and antagonists. In arterial rings placed under hypoxic conditions, the depolarizing agent KCl and veratridine, a specific Nav channels agonist, both induced a sustained contraction overlaid with rhythmic oscillations of tension. After suppression of sympathetic control either by blocking the release of catecholamine or by antagonizing the target adrenergic response, rhythmic activity persisted while the sustained contraction was abolished. This rhythmic activity of the arteries was suppressed by TTX but, in contrast, only attenuated by antagonists of calcium channels, Na+/Ca2+ exchanger, Na+/K+-ATPase and the cardiac Nav channel. These results highlight the role of Nav as a novel key element in the vasomotion of human arteries. Hypoxia promotes activation of Nav channels involved in the initiation of rhythmic oscillatory contractile activity.

Highlights

Vasomotion is a mechanism of physiological importance inherent to the smooth muscle wall observed both in vivo and in vitro
In the presence of nifedipine, oscillations could still initiate, but with lower amplitude (4.75 ± 1.07% of PE-induced contraction) and frequency (2.26 ± 0.35 min−1, n = 5) (Figure 1d). They were stopped by subsequent addition of TTX. This remarkable effect of TTX prompted us to envisage the presence of Nav channels in human arteries and their functional role in vasomotion
We demonstrated that rhythmic activity compatible with vasomotion was induced by activation of Nav channels in favorable hypoxic conditions

Summary

Introduction

Vasomotion is a mechanism of physiological importance inherent to the smooth muscle wall observed both in vivo and in vitro. It consists of rhythmic oscillations in vascular tone of blood vessels, which leads to flow motion corresponding to periodical blood flow fluctuations [1]. Vasomotion is described as a compensatory mechanism for enhancing tissue oxygenation in conditions of reduced oxygen supply, suggesting a protective role in situations where perfusion is critically limited [2,3]. Originating in the vessel wall and with low frequencies [7], oscillations of resting tone are associated with parallel and synchronized oscillations both in membrane potential and in intracellular Ca2+ concentration in SMCs [5,8]. Rhythmic oscillations in membrane potential may be recorded in SMCs [10,11,12] these cells belong to the category of non-excitable cells

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