Trophic sympathetic influence weakens pro-contractile role of Cl− channels in rat arteries during postnatal maturation

Abstract

Membrane transporters and their functional contribution in vasculature change during early postnatal development. Here we tested the hypothesis that the contribution of Cl− channels to arterial contraction declines during early postnatal development and this decline is associated with the trophic sympathetic influence. Endothelium‐denuded saphenous arteries from 1- to 2-week-old and 2- to 3-month-old male rats were used. Arterial contraction was assessed in the isometric myograph, in some experiments combined with measurements of membrane potential. mRNA and protein levels were determined by qPCR and Western blot. Sympathectomy was performed by treatment with guanethidine from the first postnatal day until 8–9-week age. Cl− substitution in the solution as well as Cl−-channel blockers (MONNA, DIDS) had larger suppressive effect on the methoxamine-induced arterial contraction and methoxamine-induced depolarization of smooth muscle cells in 1- to 2-week-old compared to 2- to 3-month-old rats. Vasculature of younger group demonstrated elevated expression levels of TMEM16A and bestrophin 3. Chronic sympathectomy increased Cl− contribution to arterial contraction in 2-month-old rats that was associated with an increased TMEM16A expression level. Our study demonstrates that contribution of Cl− channels to agonist-induced arterial contraction and depolarization decreases during postnatal development. This postnatal decline is associated with sympathetic nerves development.

Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats

“…We have shown that saphenous arteries from two-week-old L-NAME offspring have a smaller inner diameter and maximum contractility, the latter often correlating with reduced media thickness [47]. The assumption that such changes are due to a weakened trophic sympathetic influence is supported by the results of previous studies, which showed similar changes in arterial characteristics after chronic sympathectomy [14,46]. Trophic action of the sympathetic nerves was shown to increase the expression of smooth-muscle-specific α-actin and myosin [12,13], promoting the differentiation of vascular smooth muscle cells into contractile phenotypes.…”

“…The arteries of L-NAME offspring are more sensitive to methoxamine because of their sparse sympathetic innervation. Indeed, the augmented sensitivity of chronically denervated arteries to adrenoceptor agonists was shown in several studies [14,[48][49][50]. Commonly, post-denervation hypersensitivity occurs without changes in total density or the affinity of post-junctional α 1A -adrenoceptors [51,52], which have the highest affinity to methoxamine compared to B and D subtypes [33].…”

“…Presumably, the same took place in twoweek-old offspring of L-NAME-treated females, because the content of α 1A -adrenoceptor mRNA in arterial tissue was not changed by maternal L-NAME treatment. The mechanism of denervated arteries hypersensitivity downstream of the receptors may include membrane depolarization, and, consequently, the augmented activation of voltage-gated calcium channels [50] increased connexin 43 expression in smooth muscle cells and their electrical coupling [49], as well as the higher contribution of chloride channels to arterial contraction [14]. Further studies should show whether these mechanisms are also involved in increasing the adrenergic sensitivity of the sparsely innervated arteries of L-NAME offspring.…”

“…In addition to the acute vasoconstrictor effect, sympathetic nerves exert trophic action by promoting the growth of vascular smooth muscle cells, their differentiation into contractile phenotype, and consequently, vessel remodeling [11][12][13]. Of note, chronic sympathectomy reduces the maximum contractility of peripheral arteries in rats [14].…”

Chloride Ions, Vascular Function and Hypertension

“…It has been reported that the perivascular sympathetic nerves exert an abnormal trophic influence on the vascular smooth muscle membrane properties of SHRs [ 64 ], and a recent report showed that the expression and contractile function of the CaCC TMEM16A in rat arteries were reduced due to the trophic influence of sympathetic nerves during postnatal maturation [ 65 ]. Therefore, we speculate that the expression and function of CaCC TMEM16A might also be decreased along with the longer duration of hypertension in SHRs because of the persistent abnormal trophic influence of the sympathetic nerves.…”