Selective Endothelin-B Receptor Stimulation Increases Vascular Endothelial Growth Factor in the Rat Brain during Postnatal Development

Abstract

Endothelin, vascular endothelial growth factor and nerve growth factor play important roles in development of the central nervous system. ET_B receptors have been shown to promote neurovascular remodeling in the adult ischemic brain through an increase in VEGF and NGF. It is possible that ET_B receptors may be involved in postnatal development of the brain through VEGF and NGF. In the present study, the brains of male rat pups on postnatal days 1, 7, 14 and 28 were analyzed for expression of ET_B receptors, VEGF and NGF. In order to determine the effect of ET_B receptor stimulation, a separate group of pups were administered saline or ET_B receptor agonist, IRL-1620, on day 21, and their brains were analyzed on day 28. The intensity of ET_B receptor and VEGF staining in the vasculature as well as the number of blood vessels of normal pups increased with age and was significantly higher on postnatal day 14 compared to day 1 and day 7. In contrast, both ET_B and NGF staining intensity in the cortex and subventricular zones decreased (P<0.01) at postnatal day 14 compared to earlier time points. Stimulation of ET_B receptors resulted in a significant increase in VEGF and ET_B intensity both in the vasculature and the brain (P<0.05), however, IRL-1620 did not produce any change in NGF expression. Results indicate that ET_B receptors appear to play a role in the development of the CNS and selective stimulation of ET_B receptors enhances VEGF but not NGF in the postnatal rat brain.

Key words

endothelin B receptor - vascular endothelial growth factor - nerve growth factor - ontogeny - postnatal development - central nervous system

• References

• 1 Schinelli S. Pharmacology and physiopathology of the brain endothelin system: an overview. Curr Med Chem 2006; 13: 627-638
• 2 Ehrenreich H, Nau TR, Dembowski C et al. Endothelin b receptor deficiency is associated with an increased rate of neuronal apoptosis in the dentate gyrus. Neuroscience 2000; 95: 993-1001
• 3 Vidovic M, Chen MM, Lu QY et al. Deficiency in endothelin receptor B reduces proliferation of neuronal progenitors and increases apoptosis in postnatal rat cerebellum. Cell Mol Neurobiol 2008; 28: 1129-1138
• 4 Rogers SD, Demaster E, Catton M et al. Expression of endothelin-B receptors by glia in vivo is increased after CNS injury in rats, rabbits, and humans. Exp Neurol 1997; 145: 180-195
• 5 Nakagomi S, Kiryu-Seo S, Kiyama H. Endothelin-converting enzymes and endothelin receptor B messenger RNAs are expressed in different neural cell species and these messenger RNAs are coordinately induced in neurons and astrocytes respectively following nerve injury. Neuroscience 2000; 101: 441-449
• 6 Koyama Y, Michinaga S. Regulations of astrocytic functions by endothelins: roles in the pathophysiological responses of damaged brains. J Pharmacol Sci 2012; 118: 401-407
• 7 Leonard MG, Briyal S, Gulati A. Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats. Brain Res 2011; 1420: 48-58
• 8 Leonard MG, Briyal S, Gulati A. Endothelin B receptor agonist, IRL-1620, provides long-term neuroprotection in cerebral ischemia in rats. Brain Res 2012; 1464: 14-23
• 9 Leonard MG, Gulati A. Endothelin B receptor agonist, IRL-1620, enhances angiogenesis and neurogenesis following cerebral ischemia in rats. Brain Res 2013; 1528: 28-41
• 10 Hoehn BD, Harik SI, Hudetz AG. VEGF mRNA expressed in microvessels of neonatal and adult rat cerebral cortex. Brain Res Mol Brain Res 2002; 101: 103-108
• 11 Virgintino D, Errede M, Robertson D et al. VEGF expression is developmentally regulated during human brain angiogenesis. Histochem Cell Biol 2003; 119: 227-232
• 12 Rosenstein JM, Krum JM, Ruhrberg C. VEGF in the nervous system. Organogenesis 2010; 6: 107-114
• 13 Loo LS, Ng YK, Zhu YZ et al. Cortical expression of endothelin receptor subtypes A and B following middle cerebral artery occlusion in rats. Neuroscience 2002; 112: 993-1000
• 14 Lowry OH, Rosebrough NJ, Farr AL et al. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275
• 15 Briyal S, Lavhale MS, Gulati A. Repeated administration of centhaquin to pregnant rats did not affect postnatal development and expression of endothelin receptors in the brain, heart or kidney of pups. Arzneimittelforschung 2012; 62: 670-676
• 16 Quinn R. Comparing rat’s to human’s age: how old is my rat in people years?. Nutrition 2005; 21: 775-777
• 17 Gil-Mohapel J, Boehme F, Kainer L et al. Hippocampal cell loss and neurogenesis after fetal alcohol exposure: insights from different rodent models. Brain Res Rev 2010; 64: 283-303
• 18 Riechers CC, Knabe W, Siren AL et al. Endothelin B receptor deficient transgenic rescue rats: a rescue phenomenon in the brain. Neuroscience 2004; 124: 719-723
• 19 Ogunshola OO, Stewart WB, Mihalcik V et al. Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Brain Res Dev Brain Res 2000; 119: 139-153
• 20 Gora-Kupilas K, Josko J. The neuroprotective function of vascular endothelial growth factor (VEGF). Folia neuropathologica/Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 2005; 43: 31-39
• 21 Nowacka MM, Obuchowicz E. Vascular endothelial growth factor (VEGF) and its role in the central nervous system: a new element in the neurotrophic hypothesis of antidepressant drug action. Neuropeptides 2012; 46: 1-10
• 22 Li L, Xiong Y, Qu Y et al. The requirement of extracellular signal-related protein kinase pathway in the activation of hypoxia inducible factor 1 alpha in the developing rat brain after hypoxia-ischemia. Acta Neuropathol 2008; 115: 297-303
• 23 Malik S, Vinukonda G, Vose LR et al. Neurogenesis continues in the third trimester of pregnancy and is suppressed by premature birth. J Neurosci 2013; 33: 411-423
• 24 Trollmann R, Schneider J, Keller S et al. HIF-1-regulated vasoactive systems are differentially involved in acute hypoxic stress responses of the developing brain of newborn mice and are not affected by levetiracetam. Brain Res 2008; 1199: 27-36
• 25 Spinella F, Garrafa E, Di Castro V et al. Endothelin-1 stimulates lymphatic endothelial cells and lymphatic vessels to grow and invade. Cancer Res 2009; 69: 2669-2676
• 26 Spinella F, Rosanò L, Di Castro V et al. Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1alpha in human melanoma cells. Cancer Res 2007; 67: 1725-1734