Estrogen up-regulation of semaphorin 3F correlates with sympathetic denervation of the rat uterus

Richeri, Analía; Chalar, Cora; Martínez, Gaby F.; Greif, Gonzalo; Bianchimano, Paola; Brauer, M. Mónica

doi:10.1016/j.autneu.2011.06.002

Cited by 23 publications

(17 citation statements)

References 46 publications

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“…De- and re-innervation are modulated by several complex biochemical processes. Estrogen can also modulate the expression of both TrkA and p75NTR [53], but most recently, Richeri et al [54] has shown that estrogen upregulates the most effective sympathetic nerve repellent factor semaphorin 3F in rat uteri, implying that estrogen also leads to a decrease in sympathetic NFs associated with endometriosis. Chronic inflammatory diseases like rheumatoid arthritis [55,56] show semaphorin-dependent sympathetic NF depletion, which seems to be modulated through immune responses, since macrophages and other immune-competent cells, for example, release semaphorins into the inflamed tissue [55,57,58].…”

Section: Discussionmentioning

confidence: 99%

Neuroimmunomodulatory Alterations in Non-Lesional Peritoneum Close to Peritoneal Endometriosis

Arnold¹,

Vercellino²,

Chiàntera³

et al. 2012

Neuroimmunomodulation

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Objectives: An imbalance in the ratio of sensory to sympathetic nerve fibre (NF) density in peritoneal endometriotic lesions (pEL) has recently been demonstrated and leads to the assumption that this preponderance of the sensory pro-inflammatory milieu is a major cause of pain in endometriosis. Therefore, the density of sensory and sympathetic NFs was determined in distal unaffected peritoneum of endometriosis patients to be able to detect possible alterations in unaffected peritoneum. Methods: In serial pEL sections (n = 40), lesional and matching unaffected peritoneum as well as healthy peritoneum (HP) from patients without endometriosis (n = 15) were immunohistochemically analysed to identify protein gene product 9.5-, substance P- and tyrosine hydroxylase-positive NFs (intact, sensory and sympathetic NFs, respectively). In addition, the amount of immune cell infiltrates and the expression of nerve growth factor (NGF) and interleukin (IL)-1β in nerves of peritoneal endometriotic specimens were compared to those in the HP. Results: The overall NF density in the non-lesional, unaffected peritoneum of endometriosis patients is significantly reduced in comparison to both HP and pEL, while sensory NFs remain the same; the sympathetic NF density is significantly decreased compared to HP, but is still higher than the density close to the pEL. Immune cell infiltrates as well as NGF and IL-1β expression in nerves is significantly elevated in distal unaffected peritoneum in comparison to HP. Conclusion: The altered NF density in the non-lesional, unaffected peritoneum of endometriosis patients suggests new aspects in the understanding of the development of endometriosis and pain management in endometriosis.

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Section: Discussionmentioning

confidence: 99%

Neuroimmunomodulatory Alterations in Non-Lesional Peritoneum Close to Peritoneal Endometriosis

Arnold¹,

Vercellino²,

Chiàntera³

et al. 2012

Neuroimmunomodulation

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“…This decrease in CD163-ir macrophage-like cells was consistent with previous studies where vitamin D deficiency reduced proliferation and differentiation of bone marrow-derived macrophages and decreased macrophage migration (Bar-Shavit et al, 1981, Abu-Amer and Bar-Shavit, 1993), although we cannot exclude the possibility that the reduction in CD163-ir may reflect reduced expression of this scavenger receptor. Nonetheless, these findings may suggest that rather than NGF, other proteins such as semaphorins, IgLON cell adhesion molecules, and brain derived neurotrophic factor, known to be repulsive to peptidergic sensory and sympathetic axons (Miller et al, 2004, Krizsan-Agbas et al, 2008, Richeri et al, 2011), may play a role in reduced synovial innervation in vitamin D deficiency.…”

Section: 0 Discussionmentioning

confidence: 99%

Vitamin D deficiency leads to sensory and sympathetic denervation of the rat synovium

Tague

Smith

2014

Neuroscience

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Vitamin D deficiency is associated with increased susceptibility to inflammatory arthritis. Sensory and sympathetic synovial nerves are critical to the development of inflammatory arthritis and spontaneously degenerate in the early phases of disease. These nerves contain vitamin D receptors and vitamin D influences nerve growth and neurotrophin expression. We therefore examined the density of synovial nerves and neurotrophin-containing cells in vitamin D deficient rats. Seven week old Sprague Dawley rats were fed either control or vitamin D deficient diets for four weeks. Knee synovium sections extending from patella to meniscus were immunostained for total nerves, myelinated and unmyelinated nerves, sympathetic nerves, peptidergic and non-peptidergic sensory nerves, and neurotrophins and immune cell markers. In control rats, intimal innervation by unmyelinated sensory fibers was denser than subintimal innervation. In contrast, sympathetic innervation was confined to the subintima. Many sensory axons contained markers for both peptidergic and non-peptidergic nerves. NGF was primarily expressed by intimal CD163-negative type B synoviocytes, while neurturin, a ligand selective for non-peptidergic sensory neurons, was expressed by synovial mast cells. In vitamin D deficient rats, there were significant reductions in sensory nerves in the intima and sympathetic nerves in the subintima. While there was no significant change in NGF-immunoreactivity, the number of neurturin-expressing mast cells was significantly reduced in the intima, suggesting that intimal reductions in sensory nerves may be related to reductions in neurturin. Vitamin D deficiency therefore may increase susceptibility to inflammatory arthritis by depleting sensory and sympathetic synovial nerves as a result of reduced synovial neurotrophin content.

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“…In 2011, the first evidence indicating a positive correlation between the pattern and kinetics of semaphorin 3F (Sema3F) expression and estrogen-induced degeneration of uterine sympathetic nerves was reported (Richeri et al, 2011). Sema3F is a member of the vertebrate class-3 secreted semaphorins and has been shown to be repellent for sympathetic nerves (Fassold et al, 2009; Ieda and Fukuda, 2009; Fassold and Straub, 2010).…”

Section: Molecular Mechanisms Of Reproductive Tract Neuroplasticitymentioning

confidence: 99%

“…This differential time-course of expression suggests that Ntm may be involved in the initiation of nerve degeneration, while BDNF may sustain this process. Finally, Sema3F receptor NRP2 is expressed in degenerating sympathetic nerves that no longer express tyrosine hydroxylase, suggesting that this signal might act in the final stages of neurodegeneration (Richeri et al, 2011). …”

Section: Summary and Conclusion (Fig 9)mentioning

confidence: 99%

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Estrogen and female reproductive tract innervation: Cellular and molecular mechanisms of autonomic neuroplasticity

Brauer

Smith

2015

Autonomic Neuroscience

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The female reproductive tract undergoes remarkable functional and structural changes associated with cycling, conception and pregnancy, and it is likely advantageous to both individual and species to alter relationships between reproductive tissues and innervation. For several decades, it has been appreciated that the mammalian uterus undergoes massive sympathetic axon depletion in late pregnancy, possibly representing an adaptation to promote smooth muscle quiescence and sustained blood flow. Innervation to other structures such as cervix and vagina also undergo pregnancy-related changes in innervation that may facilitate parturition. These tissues provide highly tractable models for examining cellular and molecular mechanisms underlying peripheral nervous system plasticity. Studies show that estrogen elicits rapid degeneration of sympathetic terminal axons in myometrium, which regenerate under low-estrogen conditions. Degeneration is mediated by the target tissue: under estrogen's influence, the myometrium produces proteins repulsive to sympathetic axons including BDNF, neurotrimin, semaphorins, and pro-NGF, and extracellular matrix components are remodeled. Interestingly, nerve depletion does not involve diminished levels of classical sympathetic neurotrophins that promote axon growth. Estrogen also affects sympathetic neuron neurotrophin receptor expression in ways that appear to favor pro-degenerative effects of the target tissue. In contrast to the uterus, estrogen depletes vaginal autonomic and nociceptive axons, with the latter driven in part by estrogen-induced suppression BMP4 synthesis. These findings illustrate that hormonally mediated physiological plasticity is a highly complex phenomenon involving multiple, predominantly repulsive target-derived factors acting in concert to achieve rapid and selective reductions in innervation.

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Estrogen up-regulation of semaphorin 3F correlates with sympathetic denervation of the rat uterus

Cited by 23 publications

References 46 publications

Neuroimmunomodulatory Alterations in Non-Lesional Peritoneum Close to Peritoneal Endometriosis

Neuroimmunomodulatory Alterations in Non-Lesional Peritoneum Close to Peritoneal Endometriosis

Vitamin D deficiency leads to sensory and sympathetic denervation of the rat synovium

Estrogen and female reproductive tract innervation: Cellular and molecular mechanisms of autonomic neuroplasticity

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