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Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model
Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
2011 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 14, no 3, 393-405 p.Article in journal (Refereed) Published
Abstract [en]

In this study, we introduce a technique for repeated, microscopic observation of single regressing capillaries in vivo in inflamed murine corneas. Natural capillary regression was initiated by removal of inflammatory stimulus during an active pro-angiogenic phase, while the additional impact of anti-angiogenic treatment with triamcinolone or bevazicumab was investigated. Capillaries regressed naturally within 1 week and treatments did not further enhance the natural regression. Morphologically, early-phase regression was characterized by significant lumen narrowing and a significant reduction in CD11b+ myeloid cell infiltration of the extracellular matrix. By 1 week, vascular remodeling occurred concomitant with CD11b+CD68+KiM2R+ mature macrophage localization on capillary walls. Empty conduits without blood flow, positive for collagen IV and devoid of vascular endothelium and pericytes, were apparent in vivo and by 3 weeks were more numerous than perfused capillaries. By 3 weeks, macrophages aggregated around remaining perfused capillaries and were observed in apposition with degrading capillary segments. Abrupt termination of capillary sprouting in our regression model further revealed vascular endothelial abandonment of sprout tips and perfused capillary loop formation within a single angiogenic sprout, possibly as an intussusceptive response to cessation of the stimulus. Finally, we observed lumen constriction and macrophage localization on capillary walls in vivo in a clinical case of corneal capillary regression that paralleled findings in our murine model.

Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2011. Vol. 14, no 3, 393-405 p.
Keyword [en]
Inflammation, Capillary regression, In vivo confocal microscopy, Cornea
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-70325DOI: 10.1007/s10456-011-9223-3ISI: 000293922300015OAI: oai:DiVA.org:liu-70325DiVA: diva2:438352
Note
The original publication is available at www.springerlink.com: Beatrice Bourghardt Peebo, Per Fagerholm, Catharina Traneus-Rockert and Neil Lagali, Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model, 2011, Angiogenesis, (14), 3, 393-405. http://dx.doi.org/10.1007/s10456-011-9223-3 Copyright: Springer Verlag (Germany) http://www.springerlink.com/Available from: 2011-09-02 Created: 2011-09-02 Last updated: 2017-12-08
In thesis
1. Angiogenesis from a new perspective
Open this publication in new window or tab >>Angiogenesis from a new perspective
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis is the emergence of new blood and lymph vessels from existing ones. In the pathologic form it contributes to the onset and progression of numerous different human disorders such as cancer, inflammation, atherosclerosis and blinding eye diseases. There exist a number of models to study angiogenesis, both in vitro and in vivo, but there is no single perfect model so far. Consequently there is a need to develop new angiogenesis assays for evaluating blood and lymph vessel behaviour in different physiologic settings.

The aim of this thesis was to gain insight into in vivo angiogenesis introducing a new technique in an inflammatory corneal model. The method involved in vivo examination of the cornea and subsequent comparison of in vivo findings with ex vivo immunohistochemical analysis of the same tissue samples. An existing suture model for inflammatory angiogenesis in the cornea was modified for in vivo observations with a clinically-approved corneal confocal microscope.

In this thesis, corneal lymph vessels were characterized for the first time in vivo and findings from the experimental bench could be applied in a clinical setting, where presumed lymphatics were observed in a corneal transplant patient with rejection. Furthermore, the technique was extended to investigate time-lapse processes in sprouting and regressing capillaries, and led to a number of new observations. CD11b+ myeloid cells constitute the first bulk of infiltrating inflammatory cells and contribute to inflammatory sprouting and regression in numerous ways including pre-patterning of the corneal stroma and guiding of capillary sprouts. Newly formed hemangiogenic sprouts are perfused with a slow-moving fluid and have a lumen. In blood vessel regression, capillary remodeling occurred by abandonment of sprout tips in close association with macrophages and vascular loops formed by presumed intussusceptive angiogenesis. In addition, a network of pericyte- and endothelium-free basement membrane tubes was formed after desertion or degradation of vascular endothelium in former corneal capillaries.

In conclusion, we introduce a new in vivo technique for investigating angiogenesis in a corneal model were in vivo findings can be interpreted with ex vivo definitions of specific cell types by immunohistochemistry. Findings from pre-clinical experiments have been possible to apply in a clinical setting when examining patients with corneal pathology.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 91 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1284
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73137 (URN)978-91-7519-999-3 (ISBN)
Public defence
2012-01-20, Nils-Holger salen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
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Supervisors
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2014-06-05Bibliographically approved

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Bourghardt Peebo, BeatriceFagerholm, PerLagali, Neil

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Angiogenesis
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