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Genome-wide expression datasets of anti-VEGF and dexamethasone treatment of angiogenesis in the rat cornea
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.ORCID iD: 0000-0001-8722-9155
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2017 (English)In: Scientific Data, E-ISSN 2052-4463, Vol. 4, article id 170111Article in journal (Refereed) Published
Abstract [en]

Therapeutics against pathologic new blood vessel growth, particularly those targeting vascular endothelial growth factor (VEGF) are of enormous clinical interest. In the eye, where anti-VEGF agents are in widespread clinical use for treating retinal and corneal blindness, only partial or transient efficacy and resistance to anti-VEGF agents are among the major drawbacks. Conversely, corticosteroids have long been used in ophthalmology for their potency in suppressing inflammation and angiogenesis, but their broad biological activity can give rise to side effects such as glaucoma and cataract. To aid in the search for more targeted and effective anti-angiogenic therapies in the eye, we present here a dataset comparing gene expression changes in dexamethasone versus anti-Vegfa treatment of inflammation leading to angiogenesis in the rat cornea. Global gene expression analysis with GeneChip Rat 230 2.0 microarrays was conducted and the metadata submitted to Expression Omnibus repository. Here, we present a high-quality validated dataset enabling genome-wide comparison of genes differentially targeted by dexamethasone and anti-Vegf treatments, to identify potential alternative therapeutic targets for evaluation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017. Vol. 4, article id 170111
National Category
Ophthalmology Medical Genetics
Identifiers
URN: urn:nbn:se:liu:diva-140046DOI: 10.1038/sdata.2017.111ISI: 000407551900002OAI: oai:DiVA.org:liu-140046DiVA, id: diva2:1136616
Note

Funding Agencies|Swedish Research Council [2012- 2472]; Swedish Ophthalmological Society Stiftelsen Synframjandets Forskningsfond/Ogonfonden

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2019-02-11Bibliographically approved
In thesis
1. Regulation of inflammation and angiogenesis in the cornea
Open this publication in new window or tab >>Regulation of inflammation and angiogenesis in the cornea
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inflammation and angiogenesis, the growth of new blood vessels from pre-existing ones, are involved in tumor growth, ocular diseases and wound healing. In ocular angiogenesis, new pathological vessels grow into a specific eye tissue, leak fluid, and disrupt vision. The development of safe and effective therapies for ocular angiogenesis is of great importance for preventing blindness, given that current treatments have limited efficacy or are associated with undesirable side effects. The search for alternative treatment targets requires a deeper understanding of inflammation and how it can lead to angiogenesis in the eye in pathologic situations. This thesis provides new insights into the regulation of inflammation and angiogenesis, particularly at the gene expression and phenotypic levels, in different situations characterized by angiogenesis of the cornea, often called corneal neovascularization. For instance, specific genes and pathways are either endogenously activated or suppressed during active inflammation, wound healing, and during resolution of inflammation and angiogenesis, serving as potential targets to modulate the inflammatory and angiogenic response. In addition, as part of the healing response to restore corneal transparency, inflammation and angiogenesis subside with time in the cornea. In this context, LXR/RXR signaling was found to be activated in a time-dependent manner, to potentially regulate resolution of inflammation and angiogenesis. During regression of new angiogenic capillaries, ghost vessels and empty basement membrane sleeves are formed, which can persist in the cornea for a long time. Here, ghost vessels were found to facilitate subsequent revascularization of the cornea, while empty basement membrane sleeves did not revascularize. The revascularization response observed here was characterised by vasodilation, increased inflammatory cell infiltration and by sprouting at the front of the reperfused vessels. Importantly, reactive oxygen species and nitrous oxide signaling among other pro-inflammatory pathways were activated, and at the same time anti-inflammatory LXR/RXR signaling was inhibited. The interplay between activation and inhibition of these pathways highlights potential mechanisms that regulate corneal revascularization. When treating corneal neovascularization clinically, corticosteroids are in widespread use due to their effectiveness. To minimize the many undesirable side effects associated with corticosteroid use, however, identifying new and more selective agents is of great importance. Here, it was observed that corticosteroids not only suppressed pro-inflammatory chemokines and cytokines, but also activated the classical complement pathway. Classical complement may represent a candidate for further selective therapeutic manipulation to investigate its effect on treatment of corneal neovascularization.

In summary, this thesis identifies genes, pathways, and phenotypic responses involved in sprouting and remodeling of corneal capillaries, highlights novel pathways and factors that may regulate inflammation and angiogenesis in the cornea, and provides insights into regulation of capillary regression and reactivation. Further investigation of these regulatory mechanisms may offer alternative and effective treatment targets for the treatment of corneal inflammation and angiogenesis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 55
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1625
National Category
Ophthalmology Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-147979 (URN)10.3384/diss.diva-147979 (DOI)9789176852842 (ISBN)
Public defence
2018-06-01, Nils-Holger salen, Campus US, Linköping, 13:06 (English)
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Supervisors
Available from: 2018-05-21 Created: 2018-05-21 Last updated: 2019-09-30Bibliographically approved

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Mukwaya, Anthony

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Mukwaya, AnthonyMirabelli, PierfrancescoLennikov, AntonXeroudaki, MariaSchaupper, MiraPeebo, BeatriceLagali, Neil
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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Clinical and Experimental MedicineDepartment of Ophthalmology in Linköping
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