Upregulation Of The Vascular Endothelial Growth Factor, Flt-1, In Rat Hippocampal Neurons After Envenoming By Phoneutria Nigriventer; Age-related Modulation

This study characterizes the distribution and quantifies the expression of the tyrosine kinase receptor for the vascular endothelial growth factor (VEGF), Flt-1, in the rat hippocampus following intra-peritoneal injection of Phoneutria nigriventer venom (PNV). Post-natal day 14 (P14) and 8-10 weeks (adult) old rats were used and analyses were done at 1, 2, 5 and 24 h after venom exposure and compared with saline-injected counterparts. PNV-injected animals showed hippocampal venules with perivascular edema indicating blood-brain barrier (BBB) dysfunction. This was accompanied by significant overexpression of Flt-1 which though was not the same for CA1, CA2, CA3 and dentate gyrus (DG) hippocampal regions, neither for P14 and adult rats. Regional analysis using GIMP methodology showed that Flt-1 was constitutively distributed more densely in neurons of DG, followed by CA1/CA2 and CA3 of both control P14 and adult animals, without variation over time, but significantly more expressed in P14 than in adults. A time-course analysis showed that Flt-1 upregulation was progressive and that neurons VEGFR1/Flt-1+ of PNV-exposed animals are timely and regionally modulated depending on the hippocampal region, being CA2 the least responsive region regardless animal's age, whilst DG was the most susceptible with adult animals having higher upregulation than neonates. Since VEGF has been reported to confer protection in several pathological processes we suggest that VEGF may be involved in hippocampal neurons response via Flt-1 mediation following PNV envenoming; its higher upregulation in adult envenomed rats may be an indication that Flt-1 neuroprotective mediation is more efficient with age. The Flt-1 upregulation and the incidence of perivascular edema in young animals may indicate a pro-inflammatory role of the receptor. © 2012 Elsevier Ltd.604656664Altman, J., Das, G.D., Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats (1965) J. Comp. Neurol., 124, pp. 319-335Brockington, A., Lewist, C., Wharton, S., Shaw, P.J., Vascular endothelial growth factor and the nervous system (2004) Neuropathol. Appl. Neurobiol., 30, pp. 427-446Bucaretchi, F., Reinaldo, C.R.D., Hyslop, S., Madureira, P.R., de Capitani, E.M., Vieira, R.J., A clinico-epidemiological study of bites by spiders of the genus Phoneutria (2000) Rev. Inst. Med. Trop. São Paulo, 42, pp. 17-21Cameron, H.A., Woolley, C.S., McEwen, B.S., Gould, E., Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat (1993) Neuroscience, 56, pp. 337-344Choi, J.S., Kim, H.Y., Cha, J.H., Choi, J.Y., Chun, M.H., Lee, M.Y., Upregulation of vascular endothelial growth factor receptors Flt-1 and Flk-1 in rat hippocampus after transient forebrain ischemia (2007) J. Neurotrauma, 24, pp. 521-531da Cruz-Höfling, M.A., Zago, G.M., Melo, L.L., Raposo, C., C-FOS and n-NOS reactive neurons in response to circulating Phoneutria nigriventer spider venom (2007) Brain Res. Bull., 73, pp. 114-126da Cruz-Höfling, M.A., Raposo, C., Verinaud, L., Zago, G.M., Neuroinflammation and astrocytic reaction in the course of Phoneutria nigriventer (armed-spider) blood-brain barrier (BBB) opening (2009) Neurotoxicology, 30, pp. 636-646Dhondt, J., Peeraer, E., Verheyen, A., Nuydens, R., Buysschaert, I., Poesen, K., Van Geyte, K., Lambrechts, D., Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons (2011) FASEB J., 25, pp. 1461-1473Dourado, D.M., Fávero, S., Matias, R., Carvalho, P.T.C., da Cruz-Höfling, M.A., Low-level laser therapy promotes vascular endothelial growth factor receptor-1 expression in endothelial and nonendothelial cells of mice gastrocnemius exposed to snake venom (2011) Photochem. Photobiol., 87, pp. 418-426Feistritzer, C., Mosheimer, B.A., Sturn, D.H., Bijuklic, K., Patsch, J.R., Wiedermman, C.J., Expression and function of the angiopoietin receptor Tie-2 in human eosinophils (2004) J. Allergy Clin. Immunol., 114 (5), pp. 1077-1084Forstreuter, F., Lucius, R., Mentlein, R., Vascular endothelial growth factor induces chemotaxis and proliferation of microglial cells (2002) J. Neuroimmunol., 132, pp. 93-98Gomez, M.V., Kalapothakis, E., Guatimosim, C., Prado, M.A., Phoneutria nigriventer venom: a cocktail of toxins that affect ion channels (2002) Cell. Mol. Neurobiol., 22, pp. 579-588Hansen, T.M., Moss, A.J., Brindle, N.P., Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke (2008) Curr. Neurovasc. Res., 5, pp. 236-245Hoshino, M., Takahashi, M., Aoike, N., Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis (2001) J. Allergy Clin. Immunol., 107, pp. 295-301Islamov, R.R., Chintalgattu, V., Pak, E.S., Katwa, L.C., Murashov, A.K., Induction of VEGF and its Flt-1 receptor after sciatic nerve crush injury (2004) Neuroreport, 15, pp. 713-717Klausberger, T., Somogyi, P., Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations (2008) Science, 321, pp. 53-57Le Sueur, L., Kalapothakis, E., da Cruz-Höfling, M.A., Breakdown of the blood-brain barrier and neuropathological changes induced by Phoneutria nigriventer spider venom (2003) Acta Neuropathol. (Berl), 105, pp. 125-134Levison, S.W., Goldman, J.E., Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain (1993) Neuron, 10, pp. 201-212Luskin, M.B., Restricted proliferation and migration of post natally generated neurons derived from the forebrain subventricular zone (1993) Neuron, 11, pp. 173-189Olsson, A.K., Dimberg, A., Kreuger, J., Claesson-Welsh, L., VEGF receptor signaling in control of vascular function (2006) Nat. Rev. Mol. Cell Biol., 7, pp. 359-371Paxinos, G., Watson, C., (1998) The Rat Brain in Stereotaxic Coordinates, , Academic Press, San Diego, CAPoesen, K., Lambrechts, D., Van Damme, P., Dhondt, J., Bender, F., Frank, N., Bogaert, E., Carmeliet, P., Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration (2008) J. Neurosci., 28, pp. 10451-10459Rapôso, C., Zago, G.M., Silva, G.H., da Cruz-Höfling, M.A., Acute blood-brain barrier permeabilization in rats after systemic Phoneutria nigriventer venom (2007) Brain Res., 1149, pp. 18-29Ryu, J.K., Cho, T., Choi, H.B., Wang, Y.T., McLarnon, J.G., Microglial VEGF receptor response is an integral chemotactic component in Alzheimer's disease pathology (2009) J. Neurosci., 29, pp. 3-13Ruiz de Almodovar, C., Lambrechts, D., Mazzone, M., Carmeliet, P., Role and therapeutic potential of VEGF in the nervous system (2009) Physiol. Rev., 89, pp. 607-648Saab, B.J., Georgiou, J., Nath, A., Lee, F.J., Wang, M., Michalon, A., Liu, F., Roder, J.C., NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory (2009) Neuron, 63, pp. 643-656Shibuya, M., Claesson-Welsh, L., Signal transduction by VEGF receptors in regulation of angiogenesis and lymph angiogenesis (2006) Exp. Cell Res., 312, pp. 549-560Solomon, R.W., Free and open source software for manipulation of digital images (2009) AJR Am. J. Roentgenol., 192, pp. w330-33