Streptozotocin-induced diabetes differentially affects sympathetic innervation and control of plantar metatarsal and mesenteric arteries in the rat

Abstract

Johansen NJ, Tripovic D, Brock JA. Streptozotocin-induced diabetes differentially affects sympathetic innervation and control of plantar metatarsal and mesenteric arteries in the rat. Am J Physiol Heart Circ Physiol 304: H215-H228, 2013. First published November 16, 2012; doi:10.1152/ajpheart.00661.2012.-In humans neural control of arterial vessels supplying skin in the extremities is particularly vulnerable to the effects of diabetes. Here the streptozotocin (STZ) rat model of type 1 diabetes was used to compare effects on neurovascular function in plantar metatarsal arteries (PMAs), which supply blood to skin of hind paw digits, with those in mesenteric arteries (MAs). Twelve weeks after STZ (60 mg/kg ip), wire myography was used to assess vascular function. In PMAs, lumen dimensions were unchanged but both nerve-evoked contractions and sensitivity to ␣1 (phenylephrine, methoxamine)-and ␣2 (clonidine)-adrenoceptor agonists were reduced. The density of perivascular nerve fibers was also reduced by ϳ25%. These changes were not observed in PMAs from STZ-treated rats receiving either a low dose of insulin that did not greatly reduce blood glucose levels or a high dose of insulin that markedly reduced blood glucose levels. In MAs from STZ-treated rats, nerve-evoked increases in force did not differ from control but, because lumen dimensions were ϳ20% larger, nerveevoked increases in effective transmural pressure were smaller. Increases in effective transmural pressure produced by phenylephrine or ␣,␤-methylene ATP in MAs from STZ-treated rats were not smaller than control, but the density of perivascular nerve fibers was reduced by ϳ10%. In MAs, the increase in vascular dimensions is primarily responsible for reducing effectiveness of nerve-evoked constrictions. By contrast, in PMAs decreases in both the density of perivascular nerve fibers and the reactivity of the vascular muscle appear to explain impairment of neurovascular transmission. diabetes; sympathetic innervation; neurovascular transmission IN HUMANS ABNORMAL CONTROL of the vasculature has been implicated in the etiology of many diabetes-related complications such as neuropathy and diabetic foot ulceration (41). These changes involve endothelium-dysfunction (30) as well as deficits in both sympathetic nerve-mediated vasoconstriction (see below) and sensory nerve-mediated vasodilation (1). However, the mechanisms whereby diabetes affects sympathetic and sensory nerve regulation of the vasculature are not well understood, although it is believed that diabetes causes degeneration of these nerve supplies (34).Many clinical studies have evaluated the effects of diabetes on sympathetic nerve-mediated vasoconstriction of arterial vessels supplying plantar skin of the foot. These studies have demonstrated that both type 1 (insulin dependent) and type 2 (noninsulin dependent) diabetic patients with signs of sensory and/or autonomic neuropathy (e.g., orthostatic hypertension) have increased skin blood flow under basal conditions (2, 33) and attenuated reductions i...

Increased peripherin in sympathetic axons innervating plantar metatarsal arteries in STZ-induced type I diabetic rats

“…The possibility that diabetes increased NPY expression in the CGRP-IR perivascular nerve fibers can be excluded, as the CGRP-IR fibers did not co-label for NPY-IR in PMAs from either control or STZ-LI rats (Figures 5A–F). In addition, we have previously demonstrated that the density of CGRP-IR fibers in the perivascular nerve plexus is not different between PMAs from control and STZ-LI rats (Johansen et al, 2013). Importantly, diabetes increases labeling for TH-IR in the nerve plexus of PMAs (Johansen et al, 2013).…”

“…n = 8, one sample Student's t -test P < 0.05). These NPY-IR fibers are almost certainly sympathetic nerve fibers, as we have previously reported that the perivascular nerve plexus of PMAs is comprised primarily of tyrosine-hydroxylase (TH)-IR fibers, with only a small number of peptidergic primary afferent nerve fibers containing CGRP (Johansen et al, 2013). Sciatic nerve injury (Wakisaka et al, 1991, 1992; Ohara et al, 1994) has been reported to increase expression of NPY in the cell bodies of sensory neurons in dorsal root ganglia (DRG).…”

“…Most, if not all, of the axons within the nerve plexus of PMAs are β tubulin III-IR (Johansen et al, 2013). Figure 2 shows images for PMAs from a control (Figures 2A–C) and a STZ-LI rat (Figures 2E–G) immunolabeled for both β-tubulin III and peripherin.…”

“…Recently we demonstrated impaired sympathetic neurovascular transmission in plantar metatarsal arteries (PMAs) from rats with streptozotocin (STZ)-induced diabetes, a well-studied model of type I diabetes (Johansen et al, 2013). In PMAs from STZ-treated rats that received no insulin, the reduction in nerve-evoked vasoconstriction was associated with a decrease in perivascular nerve fiber density.…”

“…Microscopic studies of perivascular axons in mesenteric and tail arteries from rats with STZ-induced diabetes have not revealed any structural changes (Schmidt et al, 1988; Belai et al, 1996; Speirs et al, 2006; Johansen et al, 2013). Therefore, the sympathetic neurons supplying the PMAs appear to be selectively vulnerable to the effects of type 1 diabetes.…”