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Regulation of inflammation and angiogenesis in the cornea
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
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: urn:nbn:se:liu:diva-147979DOI: 10.3384/diss.diva-147979ISBN: 9789176852842 (print)OAI: oai:DiVA.org:liu-147979DiVA, id: diva2:1208887
Public defence
2018-06-01, Nils-Holger salen, Campus US, Linköping, 13:06 (English)
Opponent
Supervisors
Available from: 2018-05-21 Created: 2018-05-21 Last updated: 2019-09-30Bibliographically approved
List of papers
1. Factors regulating capillary remodeling in a reversible model of inflammatory corneal angiogenesis
Open this publication in new window or tab >>Factors regulating capillary remodeling in a reversible model of inflammatory corneal angiogenesis
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, p. 1-15, article id 32137Article in journal (Refereed) Published
Abstract [en]

Newly formed microcapillary networks arising in adult organisms by angiogenic and inflammatory stimuli contribute to pathologies such as corneal and retinal blindness, tumor growth, and metastasis. Therapeutic inhibition of pathologic angiogenesis has focused on targeting the VEGF pathway, while comparatively little attention has been given to remodeling of the new microcapillaries into a stabilized, functional, and persistent vascular network. Here, we used a novel reversible model of inflammatory angiogenesis in the rat cornea to investigate endogenous factors rapidly invoked to remodel, normalize and regress microcapillaries as part of the natural response to regain corneal avascularity. Rapid reversal of an inflammatory angiogenic stimulus suppressed granulocytic activity, enhanced recruitment of remodelling macrophages, induced capillary intussusception, and enriched pathways and processes involving immune cells, chemokines, morphogenesis, axonal guidance, and cell motility, adhesion, and cytoskeletal functions. Whole transcriptome gene expression analysis revealed suppression of numerous inflammatory and angiogenic factors and enhancement of endogenous inhibitors. Many of the identified genes function independently of VEGF and represent potentially new targets for molecular control of the critical process of microvascular remodeling and regression in the cornea.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-131501 (URN)10.1038/srep32137 (DOI)000381967600002 ()27561355 (PubMedID)
Note

Funding Agencies|Bayer HealthCare AB, Solna, Sweden; Swedish Research Council [2012-2472]

Available from: 2016-09-26 Created: 2016-09-23 Last updated: 2018-05-21Bibliographically approved
2. A microarray whole-genome gene expression dataset in a rat model of inflammatory corneal angiogenesis
Open this publication in new window or tab >>A microarray whole-genome gene expression dataset in a rat model of inflammatory corneal angiogenesis
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2016 (English)In: Scientific Data, E-ISSN 2052-4463, Vol. 3, article id UNSP 160103Article in journal (Refereed) Published
Abstract [en]

In angiogenesis with concurrent inflammation, many pathways are activated, some linked to VEGF and others largely VEGF-independent. Pathways involving inflammatory mediators, chemokines, and micro-RNAs may play important roles in maintaining a pro-angiogenic environment or mediating angiogenic regression. Here, we describe a gene expression dataset to facilitate exploration of pro-angiogenic, pro-inflammatory, and remodelling/normalization-associated genes during both an active capillary sprouting phase, and in the restoration of an avascular phenotype. The dataset was generated by microarray analysis of the whole transcriptome in a rat model of suture-induced inflammatory corneal neovascularisation. Regions of active capillary sprout growth or regression in the cornea were harvested and total RNA extracted from four biological replicates per group. High quality RNA was obtained for gene expression analysis using microarrays. Fold change of selected genes was validated by qPCR, and protein expression was evaluated by immunohistochemistry. We provide a gene expression dataset that may be re-used to investigate corneal neovascularisation, and may also have implications in other contexts of inflammation-mediated angiogenesis.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Oceanography, Hydrology and Water Resources
Identifiers
urn:nbn:se:liu:diva-133892 (URN)10.1038/sdata.2016.103 (DOI)000390238000001 ()27874850 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2012-2472]; Bayer HealthCare AB, Solna, Sweden; Bioinformatics Infrastructure for Life Sciences (BILS) Sweden

The publication is a peer-reviewed description of a research dataset. Aims and scope of the journal:Scientific Data primarily publishes Data Descriptors, a new type of publication that provides detailed descriptions of research datasets, including the methods used to collect the data and technical analyses supporting the quality of the measurements. Data Descriptors focus on helping others reuse data, rather than testing hypotheses, or presenting new interpretations, methods or in-depth analyses.

Available from: 2017-01-13 Created: 2017-01-13 Last updated: 2018-05-21
3. Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization
Open this publication in new window or tab >>Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization
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2018 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, no 2, p. 395-413Article in journal (Refereed) Published
Abstract [en]

Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency. Endogenous capillary regression was characterized by a progressive thinning and remodeling of angiogenic capillaries and inflammatory cell retreat in vivo in the rat cornea. By whole-genome longitudinal microarray analysis, early suppression of VEGF ligand-receptor signaling and inflammatory pathways preceded an unexpected later-phase preferential activation of LXR/RXR, PPAR alpha/RXR alpha and STAT3 canonical pathways, with a concurrent attenuation of LPS/IL-1 inhibition of RXR function and Wnt/beta-catenin signaling pathways. Potent downstream inflammatory cytokines such as Cxcl5, IL-1 beta, IL-6 and Ccl2 were concomitantly downregulated during the remodeling phase. Upstream regulators of the inflammatory pathways included Socs3, Sparc and ApoE. A complex and coordinated time-dependent interplay between pro- and anti-inflammatory signaling pathways highlights a potential anti-inflammatory role of LXR/RXR, PPAR alpha/RXR alpha and STAT3 signaling pathways in resolving inflammatory corneal angiogenesis.

Place, publisher, year, edition, pages
Springer Netherlands, 2018
Keywords
Cornea neovascularization; Inflammation; Angiogenesis; Remodeling
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-147374 (URN)10.1007/s10456-018-9604-y (DOI)000428924500016 ()29445990 (PubMedID)2-s2.0-85042119664 (Scopus ID)
Note

Funding Agencies|Swedish Research Council [2012-2472]

Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-08-02Bibliographically approved
4. Genome-wide expression differences in anti-Vegf and dexamethasone treatment of inflammatory angiogenesis in the rat cornea
Open this publication in new window or tab >>Genome-wide expression differences in anti-Vegf and dexamethasone treatment of inflammatory angiogenesis in the rat cornea
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7616Article in journal (Refereed) Published
Abstract [en]

Angiogenesis as a pathological process in the eye can lead to blindness. In the cornea, suppression of angiogenesis by anti-VEGF treatment is only partially effective while steroids, although effective in treating inflammation and angiogenesis, have broad activity leading to undesirable side effects. In this study, genome-wide expression was investigated in a suture-induced corneal neovascularization model in rats, to investigate factors differentially targeted by dexamethasone and anti-Vegf. Topical treatment with either rat-specific anti-Vegf, dexamethasone, or normal goat IgG (sham) was given to sutured corneas for 48 hours, after which in vivo imaging, tissue processing for RNA microarray, and immunofluorescence were performed. Dexamethasone suppressed limbal vasodilation (P amp;lt; 0.01) and genes in PI3K-Akt, focal adhesion, and chemokine signaling pathways more effectively than anti-Vegf. The most differentially expressed genes were confirmed by immunofluorescence, qRTPCR and Western blot. Strong suppression of Reg3g and the inflammatory chemokines Ccl2 and Cxcl5 and activation of classical complement pathway factors C1r, C1s, C2, and C3 occurred with dexamethasone treatment, effects absent with anti-Vegf treatment. The genome-wide results obtained in this study provide numerous potential targets for specific blockade of inflammation and angiogenesis in the cornea not addressed by anti-Vegf treatment, as possible alternatives to broad-acting immunosuppressive therapy.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-140047 (URN)10.1038/s41598-017-07129-4 (DOI)000407569300001 ()28811496 (PubMedID)
Note

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

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2019-04-18
5. Genome-wide expression datasets of anti-VEGF and dexamethasone treatment of angiogenesis in the rat cornea
Open this publication in new window or tab >>Genome-wide expression datasets of anti-VEGF and dexamethasone treatment of angiogenesis in the rat cornea
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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
National Category
Ophthalmology Medical Genetics
Identifiers
urn:nbn:se:liu:diva-140046 (URN)10.1038/sdata.2017.111 (DOI)000407551900002 ()
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

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