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Neuropilin-1 receptor in the rapid and selective estrogen-induced neurovascular remodeling of rat uterus

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Abstract

Sympathetic nerves innervate most organs and regulate organ blood flow. Specifically, in the uterus, estradiol (E2) elicits rapid degeneration of sympathetic axons and stimulates the growth of blood vessels. Both physiological remodeling processes, critical for reproduction, have been extensively studied but as independent events and are still not fully understood. Here, we examine the neuropilin-1 (NRP1), a shared receptor for axon guidance and angiogenic factors. Systemic estradiol or vehicle were chronically injected to prepubertal rats and uterine and sympathetic chain sections immunostained for NRP1. Uterine semaphorin-3A mRNA was evaluated by in situ hybridization. Control sympathetic uterine-projecting neurons (1-month-old) expressed NRP1 in their somas but not in their intrauterine terminal axons. Estradiol did not affect NRP1 in the distal ganglia. However, at the entrance of the organ, some sympathetic NRP1-positive nerves were recognized. Vascular NRP1 was confined to intrauterine small-diameter vessels in both hormonal conditions. Although the overall pattern of NRP1-IR was not affected by E2 treatment, a subpopulation of infiltrated eosinophil leukocytes showed immunoreactivity for NRP1. Sema3A transcripts were detected in this cellular type as well. No NRP1-immunoreactive axons nor infiltrated eosinophils were visualized in other estrogenized pelvic organs. Together, these data suggest the involvement of NRP1/Sema3A signaling in the selective E2-induced uterine neurovascular remodeling. Our data support a model whereby NRP1 could coordinate E2-induced uterine neurovascular remodeling, acting as a positive regulator of growth when expressed in vessels and as a negative regulator of growth when expressed on axons.

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Change history

  • 15 June 2020

    The article title of the original publication contains error for the term “estrogen” was captured twice.

References

  • Bogomoletz W (1980) Advantages de la coloration par le rouge Sirius de l’amyloide et des eosinophiles. Arch Anat Cytol Pathol 28:252–253

    CAS  PubMed  Google Scholar 

  • Brauer MM, Richeri A (2013) Highlights in basic autonomic neuroscience: semaphorins in the remodeling of autonomic innervation. Auton Neurosci 174:1–4

    CAS  PubMed  Google Scholar 

  • Brauer MM, Smith PG (2015) Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity. Auton Neurosci 187:1–17

    Google Scholar 

  • Brauer MM, Corbacho A, Burnstock G (1995) Effects of chronic and acute oestrogen treatment on the development of noradrenaline-containing nerves of the rat uterus. Int J Dev Neurosci 13:791–798

    CAS  PubMed  Google Scholar 

  • Carmeliet P, Tessier-Lavigne M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436:193–200

    CAS  PubMed  Google Scholar 

  • Chalar C, Richeri A, Crutcher K, Viettro L, Chávez-Genaro R, Burnstock G, Cowen T, Brauer MM (2003) Oestrogen- and sympathectomy-induced plasticity in developing uterine sensory nerves: the role of NGF. Cell Tissue Res 314:191–205

    CAS  PubMed  Google Scholar 

  • Cowen T, Thrasivoulou C (1992) A microscopical assay using densitometric application of image analysis to quantify neurotransmitter dynamics. J Neurosci Meth 45:107–116

    CAS  Google Scholar 

  • Cowen T, Woodhoo A, Sullivan C, Jolly R, Crutcher K, Wyatt S, Michael G, Orike N, Gatzinsky K, Thrasivoulou C (2003) Reduced age-related plasticity of neurotrophin receptor expression in sympathetic neurons of the rat. Aging Cell 2:59–69

    CAS  PubMed  Google Scholar 

  • Cullinan-Bove K, Koos RD (1993) Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology 133:829–837

    CAS  PubMed  Google Scholar 

  • Erskine L, François U, Denti L, Joyce A, Tillo M, Bruce F, Vargesson N, Ruhrberg C (2017) VEGF-A and neuropilin 1 (NRP1) shape axon projections in the developing CNS via dual roles in neurons and blood vessels. Development 144:2504–2516

    PubMed  PubMed Central  Google Scholar 

  • Fujisawa H (2004) Discovery of semaphorin receptors, neuropilin and plexin, and their functions in neural development. J Neurobiol 59:24–33

    CAS  PubMed  Google Scholar 

  • Gavazzi I (2001) Semaphorin-neuropilin-1 interactions in plasticity and regeneration of adult neurons. Cell Tissue Res 305:275–284

    CAS  PubMed  Google Scholar 

  • Giacobini P, Parkash J, Campagne C, Messina A, Casoni F, Vanacker C, Langlet F, Hobo B, Cagnoni G, Gallet S, Hanchate NK, Mazur D, Taniguchi M, Mazzone M, Verhaagen J, Ciofi P, Bouret SG, Tamagnone L, Prevot V (2014) Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A. PLoS Biol 12:e1001808

    PubMed  PubMed Central  Google Scholar 

  • He Z, Tessier-Lavigne M (1997) Neuropilin is a receptor for the axonal chemorepellent semaphorin III. Cell 90:739–751

    CAS  PubMed  Google Scholar 

  • Herzog Y, Kalcheim C, Kahane N, Reshef R, Neufeld G (2001) Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins. Mech Dev 109:115–119

    CAS  PubMed  Google Scholar 

  • Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580

    CAS  PubMed  Google Scholar 

  • Houdeau E, Rousseau A, Meusnier C, Prud’homme M, Rousseau J (1998) Sympathetic innervation of the upper and lower regions of the uterus and cervix in the rat have different origins and routes. J Comp Neurol 399:403–412

    CAS  PubMed  Google Scholar 

  • Hu S, Zhu L (2018) Semaphorins and their receptors: from axonal guidance to atherosclerosis. Front Physiol 9:1236

    PubMed  PubMed Central  Google Scholar 

  • Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H (1999) A requirement for neuropilin-1 in embryonic vessel formation. Development 126:4895–4902

    CAS  PubMed  Google Scholar 

  • King C, Wirth D, Workman S, Hristova K (2018) Interactions between NRP1 and VEGFR2 molecules in the plasma membrane. Biochim Biophys Acta Biomembr 1860:2118–2125

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD (1997) Neuropilin is a semaphorin III receptor. Cell 90:753–762

    CAS  PubMed  Google Scholar 

  • Krizsan-Agbas D, Pedchenko T, Smith PG (2008) Neurotrimin is an estrogen-regulated determinant of peripheral sympathetic innervation. J Neurosci Res 86(14):3086–3095

  • Lampropoulou A, Ruhrberg C (2014) Neuropilin regulation of angiogenesis. Biochem Soc Trans 42:1623–1628

    CAS  PubMed  Google Scholar 

  • Long JB, Jay SM, Segal SS, Madri JA (2009) VEGF-A and Semaphorin3A: modulators of vascular sympathetic innervation. Dev Biol 334(1):119–132

  • Makita T, Sucov HM, Gariepy CE, Yanagisawa M, Ginty DD (2008) Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons. Nature 452:759–763

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marko SB, Damon DH (2008) VEGF promotes vascular sympathetic innervation. Am J Physiol Heart Circ Physiol 294:H2646–H2652

    CAS  PubMed  Google Scholar 

  • Marone G, Varricchi G, Loffredo S, Granata F (2016) Mast cells and basophils in inflammatory and tumor angiogenesis and lymphangiogenesis. Eur J Pharmacol 778:146–151

    CAS  PubMed  Google Scholar 

  • Martínez GF, Bianchimano P, Brauer MM (2016) Estrogen-induced collagen reorientation correlates with sympathetic denervation of the rat myometrium. Auton Neurosci 201:32–39

    PubMed  Google Scholar 

  • Marzioni D, Tamagnone L, Capparuccia L, Marchini C, Amici A, Todros T, Bischof P, Neidhart S, Grenningloh G, Castellucci M (2004) Restricted innervation of uterus and placenta during pregnancy: evidence for a role of the repelling signal semaphorin 3A. Dev Dynamics 231:839–848

    CAS  Google Scholar 

  • Nangle MR, Keast JR (2011) Semaphorin 3A inhibits growth of adult sympathetic and parasympathetic neurons via distinct cyclic nucleotide signalling pathways. Br J Pharmacol 162:1083–1095

    CAS  PubMed  PubMed Central  Google Scholar 

  • Osol G, Mandala M (2009) Maternal uterine vascular remodeling during pregnancy. Physiology 24:58–71

    PubMed  Google Scholar 

  • Papka RE, Storey-Workley M, Shughrue PJ, Merchenthaler I, Collins JJ, Usip S, Saunders PT, Shupnik M (2001) Estrogen receptor-alpha and beta-immunoreactivity and mRNA in neurons of sensory and autonomic ganglia and spinal cord. Cell Tissue Res 304:193–214

    CAS  PubMed  Google Scholar 

  • Partanen TA, Makinen T, Arola J, Suda T, Weich HA, Alitalo K (1999) Endothelial growth factor receptors in human fetal heart. Circulation 100:583–586

    CAS  PubMed  Google Scholar 

  • Pavelock K, Braas K, Ouafik L, Osol G, May V (2001) Differential expression and regulation of the vascular endothelial growth factor receptors neuropilin-1 and neuropilin-2 in rat uterus. Endocrinology 142:613–622

    CAS  PubMed  Google Scholar 

  • Plein A, Fantin A, Ruhrberg C (2014) Neuropilin regulation of angiogenesis, arteriogenesis, and vascular permeability. Microcirculation 21:315–323

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rezaeepoor M, Ganjalikhani-hakemi M, Shapoori S, Eskandari N, Sharifi M, Etemadifar M, Mansuorian M (2018) Semaphorin-3A as an immune modulator is suppressed by microRNA-145-5p. Cell J 20:113–119

    PubMed  PubMed Central  Google Scholar 

  • Richeri A, Viettro L, Chavez-Genaro R, Burnstock G, Cowen T, Brauer MM (2002) Effects of infantile/prepubertal chronic estrogen treatment and chemical sympathectomy with guanethidine on developing cholinergic nerves of the rat uterus. J Histo Cyto 50:839–850

    CAS  Google Scholar 

  • Richeri A, Bianchimano P, Marmol NM, Viettro L, Cowen T, Brauer MM (2005) Plasticity in rat uterine sympathetic nerves: the role of TrkA and p75 nerve growth factor receptors. J Anat 207:125–134

    CAS  PubMed  PubMed Central  Google Scholar 

  • Richeri A, Chalar C, Bianchimano P, Greif G, Brauer MM (2008). Estrogen regulation of semaphorin expression in the rat uterus. EMBO Workshop Semaphorin Function and Mechamisms of Action, Abbaye des Vaulx de Cernay, France

  • Richeri A, Bianchimano P, Crutcher KA, Brauer MM (2010) Reduced sympathetic neurite outgrowth on uterine tissue sections from rats treated with estrogen. Cell Tissue Res 340:287–301

    CAS  PubMed  Google Scholar 

  • Richeri A, Chalar C, Martínez G, Grief G, Bianchimano P, Brauer MM (2011) Estrogen up-regulation of semaphorin 3F correlates with sympathetic denervation of the rat uterus. Auton Neurosci 164:43–50

    CAS  PubMed  Google Scholar 

  • Sastre B, Rodrigo-Muñoz JM, García-Sanchez DA, Cañas JA, del Pozo V (2018) Eosinophils: old players in a new game. J Investig Allergol Clin Immunol 28:289–304

    CAS  PubMed  Google Scholar 

  • Varricchi G, Loffredo S, Galdiero MR, Marone G, Cristinziano L, Granata F, Marone G (2018) Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol 53:152–160

    CAS  PubMed  Google Scholar 

  • Venkova K, Christov A, Kamaluddin Z, Kobalka P, Siddiqui S, Hensley K (2014) Semaphorin 3A signaling through neuropilin-1 is an early trigger for distal axonopathy in the SOD1G93A mouse model of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 73:702–713

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vo T, Carulli D, Ehlert EM, Kwok JC, Dick G, Mecollari V, Moloney EB, Neufeld G, de Winter F, Fawcett JW, Verhaagen J (2013) The chemorepulsive axon guidance protein semaphorin3A is a constituent of perineuronal nets in the adult rodent brain. Mol Cell Neurosci 56:186–200

    CAS  PubMed  Google Scholar 

  • Walter LM, Rogers PA, Girling JE (2010) Vascular endothelial growth factor-A isoform and (co) receptor expression are differentially regulated by 17beta-oestradiol in the ovariectomised mouse uterus. Reproduction 140:331–341

    CAS  PubMed  Google Scholar 

  • Yamazaki T, Li W, Mukouyama Y (2018) Whole-mount confocal microscopy for adult ear skin: a model system to study neuro-vascular branching morphogenesis and immune cell distribution. J Vis Exp. https://doi.org/10.3791/57406

  • Zoubina EV, Smith PG (2000) Axonal degeneration and regeneration in rat uterus during the estrous cycle. Auton Neurosci 84:176–185

    CAS  PubMed  Google Scholar 

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Funding

This study was funded by Fondo Clemente Estable (FCE); Agencia Nacional de Investigación e Innovación (ANII); grant number FCE_3_2016_1_126213 and Programa de Desarrollo de Ciencias Básicas (PEDECIBA-Uruguay).

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Authors and Affiliations

  1. Laboratory of Cell Biology, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Avenida Italia 3318, ZP 11600, Montevideo, Uruguay

    Analía Richeri, Gabriela Vierci, Gaby Fabiana Martínez, María Paula Latorre & María Mónica Brauer

  2. Department of Experimental Neuropharmacology, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Avenida Italia 3318, ZP 11600, Montevideo, Uruguay

    Analía Richeri

  3. Sección Bioquímica, Instituto de Biología, Facultad de Ciencias, UdelaR, Montevideo, Uruguay

    Cora Chalar

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  1. Analía Richeri
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Correspondence to Analía Richeri.

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All procedures were carried out in accordance with the Bioethics Committee guidelines, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE) (Experimental protocols ID: 001/05/2016) and following the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications N° 8023, revised 1978) and current ethical regulations under animal experimentation law N° 18.611.

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Richeri, A., Vierci, G., Martínez, G.F. et al. Neuropilin-1 receptor in the rapid and selective estrogen-induced neurovascular remodeling of rat uterus. Cell Tissue Res 381, 299–308 (2020). https://doi.org/10.1007/s00441-020-03196-8

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