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.2019 Nov;244(16):1475-1484.
doi: 10.1177/1535370219878143. Epub 2019 Sep 23.

Botulinum toxin type A suppresses arterial vasoconstriction by regulating calcium sensitization and the endothelium-dependent endothelial nitric oxide synthase/soluble guanylyl cyclase/cyclic guanosine monophosphate pathway: Anin vitro study

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Botulinum toxin type A suppresses arterial vasoconstriction by regulating calcium sensitization and the endothelium-dependent endothelial nitric oxide synthase/soluble guanylyl cyclase/cyclic guanosine monophosphate pathway: Anin vitro study

Liang Hu et al. Exp Biol Med (Maywood).2019 Nov.

Abstract

Botulinum toxin type A (BTX-A) is a potent neurotoxin that causes relaxation of striated muscle by inhibiting the release of acetylcholine at the neuromuscular junction. Some studies have suggested that BTX-A treatment for Raynaud syndrome is safe and effective with few adverse reactions. However, the underlying mechanism remains unclear. In the present study, we used both arterial rings isolated from rabbits and human microvascular endothelial cells (HMEC-1) to evaluate the mechanism underlying the effects of BTX-A on arterial vasoconstriction induced by 5-hydroxytryptamine. The roles of calcium sensitization and the endothelial nitric oxide synthase (eNOS)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway were investigated. BTX-A caused a concentration-dependent decrease in the contraction of endothelium-intact arteries and significantly reduced calcium sensitization in the arteries. Inhibitors of eNOS (L-NAME) and sGC (methylene blue) both significantly abolished the vasodilatory action of BTX-A. Furthermore, BTX-A increased eNOS activity and the cGMP level in dose- and time-dependent manners and increased eNOS and sGC protein levels in a time-dependent manner in HMEC-1. Taken together, these findings indicate that BTX-A suppresses arterial vasoconstriction by regulating smooth muscle calcium sensitization and the eNOS/sGC/cGMP pathway.

Impact statement: Raynaud syndrome (RS), usually caused by cold or mental stress, may lead to cyanosis and reactive hyperemia accompanied by pain or paresthesia. Although a variety of drugs have been used to alleviate the symptoms, the effects have not been satisfactory, so there is an urgent need to explore new alternative treatments. The present study investigated the mechanism underlying the effects of botulinum toxin type A (BTX-A) on arterial vasoconstriction, which may provide new approaches for RS. We found that BTX-A suppresses arterial vasoconstriction by regulating smooth muscle calcium sensitization and the endothelial nitric oxide synthase (eNOS)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. These findings clarify the underlying mechanism of the effects of BTX-A on arterial vasoconstriction and provide new theoretical support for the use of BTX-A on RS. It may also help us to develop new medicines which regulate calcium sensitization and the eNOS/sGC/cGMP pathway against RS.

Keywords: Botulinum toxin type A; artery vasoconstriction; calcium sensitization; cyclic guanosine monophosphate; endothelial nitric oxide synthase; smooth muscle cell; soluble guanylyl cyclase.

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Figures

Figure 1.
Figure 1.
Effect of BTX-A on aortic resting tension and 5-HT-inducedvasoconstriction. (a) The effect of BTX-A on arterial resting tension inthe absence versus presence of the endothelium; −Endo group was used asControl. (b) The effect of BTX-A on 5-HT-induced vasoconstriction; BTX-A0 IU/mL was used as Control. (c) The effect of the interaction of BTX-Aand the endothelium on vasoconstriction; −Endo group was used asControl. −Endo: arterial ring without endothelium; + Endo: arterial ringwith endothelium. + Endo + BTX-A: arterial ring with endothelium treatedwith 20 IU/mL BTX-A; −Endo + BTX-A: arterial ring without endotheliumtreated with 20 IU/mL BTX-A.# p < 0.05 compared with the−Endo group or with the 0 IU/mL BTX-A group. N = 8. BTX-A: botulinum toxin type A; 5-HT: 5-hydroxytryptamine.
Figure 2.
Figure 2.
Effect of BTX-A on arterial ring diameter and myogenic tone. Differencesin arterial ring diameter (a), myogenic tone (b), and calcium content(c) between the Control and BTX-A groups. (d) Difference in myogenictone between the Control and BTX-A groups in the presence of calcium.# p < 0.05 compared with the Control group. N = 8. BTX-A: botulinum toxin type A.
Figure 3.
Figure 3.
Calcium sensitization of permeabilized arterioles after BTX-A treatment.Myogenic tone in arterioles (a) and calcium sensitivity (b) in theControl and BTX-A groups. A decrease in calcium sensitivity was detectedafter BTX-A treatment. The effective concentration that produced halfmaximal constriction (EC50) was significantly higher for arterioles inthe BTX-A group than the Control group.# p < 0.05compared with the Control. N = 8. BTX-A: botulinum toxin type A.
Figure 4.
Figure 4.
Effect of inhibitors of eNOS and sGC on the vasodilatory action of BTX-A.The effects of an inhibitor of eNOS (L-NAME) (a) and an inhibitor of sGC(MB) (b) on the vasodilatory action of BTX-A. (c) The effects of BTX-A,L-NAME, and MB on vascular diameter.& p < 0.05compared with the BTX-A group. N = 8. BTX-A: botulinum toxin type A; 5-HT: 5-hydroxytryptamine; MB: methyleneblue.
Figure 5.
Figure 5.
Effects of BTX-A on eNOS activity and cGMP levels in HMEC-1. Effects ofthe BTX-A concentration and treatment duration on endothelial eNOSactivity were shown in Figure 5(a) and (b). Effects of the BTX-A concentration andtreatment duration on cGMP level were shown in Figure 5(c) and (d). In Figure 5(a) and(c), BTX-A 0 IU/mL was used as Control; in Figure 5(b) and(d), 0 min was used as Control.# p < 0.05compared with the 0 IU/mL BTX-A (a and c) or 0 min ((b) and (d)) group.N = 8. BTX-A: botulinum toxin type A; cGMP: cyclic guanosine monophosphate;eNOS: endothelial nitric oxide synthase.
Figure 6.
Figure 6.
Effects of BTX-A on eNOS and sGC protein levels in HMEC-1. Effects of theBTX-A treatment duration on eNOS (a) and sGC (b) protein levels. 0 minwas used as Control.# p < 0.05 compared with the 0 mingroup. N = 8. eNOS: endothelial nitric oxide synthase; GAPDH:glyceraldehyde-3-phosphate dehydrogenase; sGC: soluble guanylylcyclase.
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