Ageing alters perivascular nerve function of mouse mesenteric arteries in vivo

Abstract

Key points• Neural control of the circulation is integral to the regulation of tissue blood flow and systemic blood pressure. Vascular dysfunction occurs with ageing but little is known of corresponding changes in the role(s) of perivascular nerves.• We developed a preparation to study intact mesenteric arteries (MAs) in anaesthetized mice to investigate age-related changes in the function of perivascular sympathetic and sensory nerves in vivo.• Ageing decreased the diameter of MAs, reduced their sensitivity to α 1 -adrenoreceptor stimulation and impaired the ability of sensory nerves to attenuate sympathetic vasoconstriction.• These changes were manifest in males and females and were unaffected by the expression of the GCaMP2 transgene in endothelial cells, confirming the utility of this model.• Our results imply that ageing imposes structural and functional limitations to the splanchnic circulation that impair the ability to mobilize blood from the gut in times of physical stress.Abstract Mesenteric arteries (MAs) are studied widely in vitro but little is known of their reactivity in vivo. Transgenic animals have enabled Ca 2+ signalling to be studied in isolated MAs but the reactivity of these vessels in vivo is undefined. We tested the hypothesis that ageing alters MA reactivity to perivascular nerve stimulation (PNS) and adrenoreceptor (AR) activation during blood flow control. First-(1A), second-(2A) and third-order (3A) MAs of pentobarbital-anaesthetized Young (3-6 months) and Old (24-26 months) male and female Cx40 BAC -GCaMP2 transgenic mice (C57BL/6 background; positive or negative for the GCaMP2 transgene) were studied with intravital microscopy. A segment of jejunum was exteriorized and an MA network was superfused with physiological salt solution (pH 7.4, 37• C). Resting tone was ≤ 10% in MAs of Young and Old mice; diameters were ∼5% (1A), 20% (2A) and 40% (3A) smaller (P ≤ 0.05) in Old mice. Throughout MA networks, vasoconstriction increased with PNS frequency (1-16 Hz) but was ∼20% less in Young vs. Old mice (P ≤ 0.05) and was inhibited by tetrodotoxin (1 μM). Capsaicin (10 μM; to inhibit sensory nerves) enhanced MA constriction to PNS (P ≤ 0.05) by ∼20% in Young but not Old mice. Phenylephrine (an α 1 AR agonist) potency was greater in Young mice (P ≤ 0.05) with similar efficacy (∼60% constriction) across ages and MA branches. Constrictions to UK14304 (an α 2 AR agonist) were less (∼20%; P ≤ 0.05) and were unaffected by ageing. Irrespective of sex or transgene expression, ageing consistently reduced the sensitivity of MAs to α 1 AR vasoconstriction while blunting the attenuation of sympathetic vasoconstriction by sensory nerves. These findings imply substantive alterations in splanchnic blood flow control with ageing.

Rat mesenteric small artery neurogenic dilatation is predominantly mediated by β1‐adrenoceptors in vivo

“…However, the effect appears to be limited, as indicated by the lack of significant effect of BIBN4096bs on the vasoconstrictor responses to EFS. This finding contrasts with the significant effect of capsaicin on the vasoconstrictor response to EFS in rat mesenteric arteries (Westcott & Segal, ; Boerman & Segal, ), in the perfused rat mesenteric bed (Hatanaka et al . ), in rat vas deferens (Donoso et al .…”

“…). Furthermore, intravital microscopy has been used to describe alterations in sensory‐motor nerves with ageing (Westcott & Segal, , b ). In organ bath studies with isolated artery segments, EFS‐induced vasodilatation is tetrodotoxin (TTX) insensitive (Hardebo et al .…”

Depressed perivascular sensory innervation of mouse mesenteric arteries with advanced age

“…and ) and altered RAMP1 distribution in ECs of MAs from Old versus Young mice (Fig. ), the impaired functional role for perivascular sensory nerves in the intact system (Westcott & Segal, a ) further reflects a decrease in neuropeptide availability and altered receptor function. Thus, ageing exerts a multifaceted effect on suppressing the role of sensory nerves in mediating vasodilatation along with their ability to attenuate sympathetic vasoconstriction.…”

“…Advanced age decreases perivascular sensory nerve function of MAs controlling blood flow to the small intestine of mice (Westcott & Segal, a ). The present study used isolated MAs to gain insight into the mechanisms underlying this functional deficit.…”

“…In mesenteric arteries (MAs) of the anaesthetized mouse, advanced age (e.g. ß24 versus 4 months; corresponding to mid-60 s and mid-20 s, respectively, in humans; Flurkey et al 2007) was found to enhance sympathetic vasoconstriction in association with a diminished role for sensory nerves (Westcott & Segal, 2013a). However, the mechanism underlying such changes is unknown.…”