Mione, Maria Caterina; (1991) Plasticity of perivascular nerves. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis presents a study on the plasticity of perivascular nerves, and is divided in two sections. The first concerns changes in expression of perivascular nerves during development and ageing and in the nerves that remain after selective sympathetic and/or sensory denervation of the rat cerebral, meningeal and irideal vessels. In the second section changes in the innervation of the guinea pig uterine artery during pregnancy and after chronic treatment with progesterone are described. Changes in the expression of neurotransmitters in cerebrovascular nerves were studied in rats from birth to 27 months of age, using histochemical and immunohistochemical techniques, followed by quantitative analysis of the density of innervation. The study revealed an early development of sympathetic cerebrovascular nerves, while sensory nerves and parasympathetic nerves developed later. Ageing resulted in a decrease of the expression of vasoconstrictor neurotransmitters in cerebrovascular nerves, whereas the expression of vasodilator neurotransmitters (vasoactive intestinal polypeptide, VIP, and calcitonin gene-related peptide, CGRP) was strikingly increased. Long-term sympathectomy produced by chronic treatment with guanethidine caused degeneration of the sympathetic neurons in the superior and inferior cervical ganglia and disappearance of glyoxylic acid-induced fluorescent nerves and 5-hydroxydopamine (5-OHDA) labelled vesicles in rat cerebral, meningeal and irideal vessels. The results also suggest that there is a compensatory increase of the expression of neuropeptide Y (NPY)-immunoreactivity (IR) in non-sympathetic perivascular axons in the brain and iris of developing rats subjected long-term guanethidine treatment, but not in those of the dura mater. Using a dual immunostaining technique at the ultrastructural level, the NPY-IR present in cerebrovascular nerves of developing rats sympathectomized with long-term guanethidine treatment was localized in VIP-IR nerve fibres. Their origin, from pterygopalatine ganglion neurons, was traced using a fluorescent neuronal tracer (fast blue) and immunohistochemistry revealed an increase in the expression of NPY-IR in pterygopalatine ganglion neurons after long-term sympathectomy. An increased number of CGRP- and substance P (SP)-IR nerves was observed in the anterior cerebral artery, iris and dura mater of guanethidine sympathectomized rats. These nerve fibres could arise from sensory and/or parasympathetic cranial neurons storing CGRP- and/or SP-LI. Rats were also subjected to long-term guanethidine treatment afer capsaicin treatment. Projection of sensory CGRP- , but not SP-IR neurons which did not degenerate after capsaicin treatment again increased dramatically after guanethidine treatment. In the second section of this thesis, the number of noradrenaline (NA)-containing nerves in the uterine artery, which formed the densest plexus in virgin animals, was much reduced in late pregnancy, a finding supported by a significant reduction in noradrenaline levels. In contrast, the innervation of the uterine artery by NPY-IR nerve fibres was increased in pregnancy, while the other peptidergic nerves and peptide levels were unchanged. Systemic progesterone treatment did not mimic these changes. An immunocytochemical analysis of uterine arteries from virgin and pregnant guinea-pigs injected with 5-OHDA to label noradrenergic nerves showed that, unlike the pregnant uterus, no degeneration of nerves containing large and small dense-cored vesicles occurred in pregnant uterine arteries. The results suggested that, in pregnant animals, 5-OHDA labelled vesicles were also present in non-noradrenergic perivascular nerves. In the uterine arteries from pregnant guinea-pigs, the neuronal uptake of 3H-NA was found to be increased compared with that of control arteries, despite the reduction of noradrenergic nerves. The autoradiographic localization of 3H-NA taken up by guinea pig uterine arteries, further processed for immunocytochemistry of dopamine β hydroxylase (DBH)-, NPY-, VIP-, SP- and CGRP-IR, revealed that the uptake of 3H-NA in pregnant animals occurred also in non-sympathetic nerves. This study showed that : a) compensatory changes in the expression of neurotransmitters in perivascular nerves occur both in physiological (development, aging, pregnancy) and experimental (selective denervation) conditions; b) the changes that have been observed are complex: one clear example is a marked increase in CGRP/SP in sensory nerves following destruction of sympathetic nerves; another is the increase of NPY in perivascular nerves supplying the uterine artery in late pregnancy; c) plasticity is a property of perivascular nerves that is retained throughout life.

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