Endothelin-1-Induced Signaling Involved in Extracellular Matrix Remodeling

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dc.contributor.advisorThomas Yorio
dc.contributor.committeeMemberNeeraj Agarwal
dc.contributor.committeeMemberPeter Koulen
dc.creatorHe, Shaoqing
dc.date.accessioned2019-08-22T21:10:40Z
dc.date.available2019-08-22T21:10:40Z
dc.date.issued2006-12-01
dc.date.submitted2013-08-27T13:28:54-07:00
dc.description.abstractET-1-Induced Signaling in ECM Remodeling in Astrocytes. Shaoqing He, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107. ET-1 levels are elevated under pathophysiological conditions, including glaucoma, however, ET-1’s ocular functions are not fully documented. Therefore, ET-1-induced signaling and ECM remodeling in astrocytes and at the optic nerve head were determined in this study. Three signaling pathways, including ERK1/2, PKC, and P13 kinase, were involved in ET-1-medicated cell proliferation of U373MG astrocytoma cells. Blocking one of these pathways completely abolished cell proliferation. It appeared that ERK1/2 activation was involved, but was independent of PKC and P13 kinase activation by ET-1. It was also determined that the ETB receptor was the dominant receptor involved in ERK1/2 phosphorylation and cell proliferation. In addition, ERK1/2 phosphorylation was not transactivated by the EGF receptor by ET-1. The studies also indicated that there was no activation of c/nPKC, although PKC was involved in cell proliferation. In U373MG astrocytoma cells, MAPK-ERK, PKC and P13K pathways appear to exert their roles in parallel without a direct, apparent “cross-talk”. Based on the signaling pathways obtained from U373MG astrocytoma cells, the regulation of MMPs/TIMPs and fibronectin in ET-1-activated human optic nerve head astroctyes (hONAs) was also determined. ET-1 not only induced rapid phosphorylation of ERK1/2 and PKC βI/ βII/δ but also increased the activity of MMP-2 and the expression of TIMP=1 and 2. The activity of MMP-2 was enhanced in the presence of inhibitors of MAPK or PKC in hONAs, whereas the expression of TIMP-1 and 2 was abolished. ET-1 increased the soluble fibronectin (FN) expression as well as FN matrix formation, however, the expression and deposition of FN were MAPK- and PKC-independent, whereas expression and activity of MMps and TIMPs were MAPK- and PKC-dependent. Therefore, ET-1 shifted the balance of MMPs/TIMPs and substrates that altered the ECM composition and subsequently let to ECM remodeling in activated hONA cells. ET-1’s effects on ECM remodeling at the optic nerve head were also examined following intravitreal administration of ET-1 in rats. The increased expression of MMP-9 and collagen VI was detected in both ETB deficient rats and wildtype Wistar rats post ET-1 intravitreal injection for 2 and 14 days, whereas the deposition of FN and collagen IV was unchanged. There was no significant difference in staining of MMP-9 and collagen VI between ETB deficient rats and wildtype Wistar rats. In this study, ECM remodeling was demonstrated in rats injected with ET-1 into the vitreous. Such changes in the ECM seen in the current study provide additional insight into the mechanisms that might explain the glaucomatous changes observed in ET-1-injection or perfusion models. In summary, ET-1 not only activated several signaling pathways in cell proliferation of astrocytes, but also modulated the expression of ECM molecules in vitro and in vivo, indicating that ET-1 plays a regulatory role in ECM remodeling. These effects coupled with observations that ET-1 levels are elevated in glaucoma patients, suggests that ET-1 may be involved in glaucomatous optic neuropathy.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29131
dc.language.isoen
dc.provenance.legacyDownloads1
dc.subjectCell and Developmental Biology
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.subjectEye Diseases
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.subjectMolecular and Cellular Neuroscience
dc.subjectNervous System
dc.subjectNeuroscience and Neurobiology
dc.subjectOphthalmology
dc.subjectOther Cell and Developmental Biology
dc.subjectOther Neuroscience and Neurobiology
dc.subjectPhysiology
dc.subjectSignal Processing
dc.subjectSystems and Integrative Physiology
dc.subjectSystems Neuroscience
dc.subjectVision Science
dc.subjectET-1
dc.subjectpathophysiological conditions
dc.subjectocular functions
dc.subjectcell proliferation
dc.subjectU33MG astrocytoma
dc.subjectERK1/2
dc.subjectPKC
dc.subjectECM Remodeling
dc.subjectAstrocytes
dc.subjectphosphorylation
dc.subjectsoluble fibronectin
dc.subjectrats
dc.subjectcollagen VI
dc.subjectglaucoma
dc.subjectoptic neuropathy
dc.titleEndothelin-1-Induced Signaling Involved in Extracellular Matrix Remodeling
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplinePharmacology and Neuroscience
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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