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

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 -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.

Tetrodotoxin Decreases the Contractility of Mesenteric Arteries, Revealing the Contribution of Voltage-Gated Na+ Channels in Vascular Tone Regulation

“…Our data showed that Na V channels are expressed in both endothelium and media of murine FOMA and CA in agreement with previous investigations performed on murine cremaster arteries [ 13 ], human subcutaneous arterioles [ 21 ], and human uterine arteries [ 15 ]. Our RT-qPCR data indicate that scn2a , encoding Na V 1.2, is the most abundant Na V channel α-subunit gene expressed in both aorta and MA.…”

“…In addition, scn2b and scn3b are also expressed but to a much lower extent. Indeed, the expression of Na V β subunits has hardly ever been studied in arteries, but similar to our data, scn1b , scn2b , and scn3b expressions have been reported in rat aorta [ 6 ], while scn1-4b are expressed in human uterine arteries [ 15 ]. Altogether, it seems that the expression profile of the Na V channel gene in arteries is different in rodents and humans.…”

“…The Na V channel gene, scn2a is also well expressed in mouse cremaster [ 13 ] and femoral arteries, the MA and aorta from rats [ 6 , 9 ]. However, in humans, scn9a encoding Na V 1.7 is the vascular Na V channel isoform expressed in both uterine arteries and subcutaneous arterioles [ 15 , 21 ], but this subtype has not been detected in our mouse arteries. The scn3a transcript, encoding Na V 1.3, is present in the aorta, but at a low level, suggesting that this subtype could be weakly expressed at the protein level.…”

“…In the vasculature, Na V channels are expressed and generate Na + currents in both endothelial cells (EC) and vascular smooth muscle cells (VSMC) isolated from the aorta, pulmonary, mesenteric, coronary, uterine, and cremaster arteries [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Their involvement in vascular contractility has been demonstrated in rat mesenteric arteries (MA) [ 9 ].…”

Effective Perturbations by Small-Molecule Modulators on Voltage-Dependent Hysteresis of Transmembrane Ionic Currents

“…The results presented herein are interesting, and they hence led us to propose that, in concert with its antagonistic action of mineralocorticoid receptor, the exposure to esaxerenone may directly modify the magnitude, gating properties, and Hys (V) strength of I Na present in different excitable cells. It also needs to be mentioned that the activity of Na V channels has been found to be functionally expressed in various types of vascular smooth muscles [ 84 , 85 ]. Therefore, it is worth pursuing to a further extent as to which esaxerenone-induced antihypertensive action [ 78 , 79 ] is associated with its additional inhibitory action on I Na (i.e., Na V 1.7-encoded current) inherently in vascular smooth myocytes.…”