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      Hyperinnervation of Mesenteric Arteries in Spontaneously Hypertensive Rats by Sympathetic but Not Primary Afferent Axons

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          Abstract

          Hypertrophy of the perivascular plexus is thought to play a role in the development of hypertension in spontaneously hypertensive rats (SHR). However, it is not known whether the sympathetic varicosities are more numerous or larger, or form more neurovascular junctions. Further, a parallel hypertrophy of primary afferent terminals around the vessels might modulate any effects of hypertrophied sympathetic terminals. We have investigated the perivascular plexus around second-order mesenteric arteries of SHR and Wistar-Kyoto (WKY) rats by electron microscopy. Noradrenergic terminals were identified by the presence of small granular vesicles after chromaffin fixation, and substance P (SP+) afferent axons were identified by immunohistochemistry. The numbers of noradrenergic axon and varicosity profiles were higher (48 and 25%, respectively) in SHR than in WKY rats, and the majority lay closer to the medio-adventitial border. In contrast, there was no difference in the numbers of SP+ axons. Sympathetic and SP+ varicosities were indistinguishable in size, shape, vesicle content and mitochondrion content between each other and between the strains. However, both the number of neuromuscular junctions and the proportion of varicosities that formed them in SHR arteries were more than double those in WKY vessels. The data clearly show that hyperinnervation in SHR is specific for noradrenergic axons.

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          Most cited references 25

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          Nerve growth factor receptor TrkA is down-regulated during postnatal development by a subset of dorsal root ganglion neurons.

          Nerve growth factor (NGF), signaling through its receptor tyrosine kinase, TrkA, is required for the survival of all small and many intermediate-sized murine dorsal root ganglion (DRG) neurons during development, accounting for 80% of the total DRG population. Surprisingly, NGF/TrkA-dependent neurons include a large population that does not express TrkA in adult mice (Silos-Santiago et al., 1995). This finding suggests two hypotheses: Neurons lacking TrkA in the adult may express TrkA during development, or they may be maintained through a paracrine mechanism by TrkA-expressing neurons. To determine whether TrkA is expressed transiently by DRG neurons that lack the receptor in adulthood, we examined the distribution of TrkA protein during development. We show here that TrkA expression is strikingly developmentally regulated. Eighty percent of DRG neurons expressed TrkA during embryogenesis and early postnatal life, whereas only 43% expressed TrkA at postnatal day (P) 21. Because the period of TrkA down-regulation corresponds with a critical period during which nociceptive phenotype can be altered by NGF (see Lewin and Mendell [1993] Trends Neurosci. 16:353-359), we examined whether NGF modulates the down-regulation of TrkA. Surprisingly, neither NGF deprivation nor augmentation altered the extent of TrkA down-regulation. Our results demonstrate a novel form of regulation of neurotrophin receptor expression that occurs late in development. All DRG neurons that require NGF for survival express TrkA during embryogenesis, and many continue to express TrkA during a postnatal period when neuronal phenotype is regulated by NGF. The subsequent down-regulation of TrkA is likely to be importantly related to functional distinctions among nociceptive neurons in maturity.
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            Postnatal changes in the expression of the trkA high-affinity NGF receptor in primary sensory neurons.

            In development approximately 70-80% of dorsal root ganglion (DRG) cells are dependent on nerve growth factor (NGF) for their survival, while in the adult only some 40% of DRG cells express the high-affinity NGF receptor, trkA. This discrepancy suggests that trkA expression, and therefore neurotrophin sensitivity, may alter as the animal matures. We have tested this possibility by counting the number of L4/5 DRG neurons showing immunoreactivity for trkA in rats from the day of birth to postnatal day 14. We also examined changes in p75 and IB4 labelling. On the day of birth, 71% of DRG cells were found to express trkA. However, this percentage gradually fell with age and reached adult levels at postnatal day 14. The expression of p75 did not parallel that of trkA, remaining relatively constant at between 45 and 50% of cells from birth to postnatal day 14. Over the same period there was a marked increase in the proportion of cells which bind the lectin IB4 from 9 (day of birth) to 40% (day 14). Since in the adult the IB4 population consists of small cells which mostly do not express trkA, this finding suggests that the postnatal down-regulation of trkA occurs in this population. Consistent with this suggestion are the results of double labelling for trkA and IB4, which confirmed that at times intermediate between birth and postnatal day 14 there was a high degree of coexpression between these markers (which is absent in the adult). This result also suggests that the down-regulation of trkA is unlikely to be directly responsible for the emerging IB4 binding.
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              Effect of endothelium on the actions of sympathetic and sensory nerves in the perfused rat mesentery.

              We and others have previously demonstrated that pretreatment with capsaicin produces an augmentation of vasoconstrictor responses to transmural nerve stimulation. In the present study, removal of endothelium by saponin or inhibition of nitric oxide synthesis by N omega-nitro-L-arginine methyl ester produced an augmentation of vasoconstrictor responses to transmural nerve stimulation, responses which were further potentiated after treatment with capsaicin to desensitize sensory nerves. Capsaicin treatment decreased vasodilator responses to acetylcholine, but only at low acetylcholine concentrations. Potentiation by capsaicin of vasoconstrictor responses to transmural nerve stimulation was not affected by indomethacin. In the presence of guanethidine and methoxamine, transmural nerve stimulation caused vasodilator responses in the perfused rat mesentery. These responses were unaffected by removal of endothelium, as were vasodilator responses to exogenous calcitonin gene-related peptide (CGRP). In contrast, substance P did not produce any relaxation in the methoxamine-contracted mesentery. This study suggests that facilitation of vasoconstrictor responses to transmural nerve stimulation after capsaicin treatment primarily reflects inhibition of sensory nerve effects resulting in an increase of sympathetic vasoconstrictor actions. The present results also suggest that vasodilator responses to sensory nerve activation or exogenous CGRP are endothelium-independent and that substance P does not significantly contribute to modulation of vascular tone in the rat mesentery.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2005
                August 2005
                29 July 2005
                : 42
                : 4
                : 348-358
                Affiliations
                aMonash Micro Imaging, School of Biomedical Science, Monash University, Clayton, and bPrince of Wales Medical Research Institute and University of New South Wales, Randwick, Australia
                Article
                86886 J Vasc Res 2005;42:348–358
                10.1159/000086886
                16015033
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, Tables: 3, References: 39, Pages: 11
                Categories
                Research Paper

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