Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. 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.
Univ Tubingen, Germany.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Show others and affiliations
2019 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, no 7, p. 1402-1418Article in journal (Refereed) Published
Abstract [en]

Objective—

Pathological neovascularization is crucial for progression and morbidity of serious diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. While mechanisms of ongoing pathological neovascularization have been extensively studied, the initiating pathological vascular remodeling (PVR) events, which precede neovascularization remains poorly understood. Here, we identify novel molecular and cellular mechanisms of preneovascular PVR, by using the adult choriocapillaris as a model.

Approach and Results—

Using hypoxia or forced overexpression of VEGF (vascular endothelial growth factor) in the subretinal space to induce PVR in zebrafish and rats respectively, and by analyzing choriocapillaris membranes adjacent to choroidal neovascular lesions from age-related macular degeneration patients, we show that the choriocapillaris undergo robust induction of vascular intussusception and permeability at preneovascular stages of PVR. This PVR response included endothelial cell proliferation, formation of endothelial luminal processes, extensive vesiculation and thickening of the endothelium, degradation of collagen fibers, and splitting of existing extravascular columns. RNA-sequencing established a role for endothelial tight junction disruption, cytoskeletal remodeling, vesicle- and cilium biogenesis in this process. Mechanistically, using genetic gain- and loss-of-function zebrafish models and analysis of primary human choriocapillaris endothelial cells, we determined that HIF (hypoxia-induced factor)-1α-VEGF-A-VEGFR2 signaling was important for hypoxia-induced PVR.

Conclusions—

Our findings reveal that PVR involving intussusception and splitting of extravascular columns, endothelial proliferation, vesiculation, fenestration, and thickening is induced before neovascularization, suggesting that identifying and targeting these processes may prevent development of advanced neovascular disease in the future.

Visual Overview—

An online visual overview is available for this article.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2019. Vol. 39, no 7, p. 1402-1418
Keywords [en]
choroidal neovascularization; hypoxia; intussusception; macular degeneration; zebrafish
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-158946DOI: 10.1161/ATVBAHA.118.312190ISI: 000472969200016PubMedID: 31242036Scopus ID: 2-s2.0-85068847736OAI: oai:DiVA.org:liu-158946DiVA, id: diva2:1338184
Note

Funding Agencies|Crown Princess Margareta Association for the Visually Impaired; Edwin Jordan Foundation; Swedish Eye Foundation; Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Eva och Oscar Ahrens Stiftelse; Ollie och Elof Ericssons Stiftelse; Carmen och Bertil Ragners Stiftelse; Gosta Fraenkels Stiftelse; Ake Wibergs Stiftelse; Lions Forskningsfond; Karin Sandbergs Stiftelse; Cancerfonden; Karolinska Institutets Stiftelser och Fonder; Vetenskapsradet

Available from: 2019-07-20 Created: 2019-07-20 Last updated: 2019-11-12Bibliographically approved

Open Access in DiVA

fulltext(1282 kB)7 downloads
File information
File name FULLTEXT01.pdfFile size 1282 kBChecksum SHA-512
44c27d3951a6002f62415f21c07ac32c8e4fe7c550f4d573c79690e97ecdc48ace115d42b5b5b1ae93aced92e9b2e690f341aa4c90abe9af9a237d46cfee880c
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMedScopus

Search in DiVA

By author/editor
Ali, ZaheerMukwaya, AnthonnyNtzouni, MariaLennikov, AntonHildesjö, CamillaPeebo, BeatriceLagali, NeilJensen, Lasse
By organisation
Division of Cardiovascular MedicineFaculty of Medicine and Health SciencesDivision of Neuro and Inflammation ScienceDivision of Cell BiologyDivision of Surgery, Orthopedics and OncologyClinical pathologyDepartment of Ophthalmology in LinköpingDepartment of Clinical Pharmacology
In the same journal
Arteriosclerosis, Thrombosis and Vascular Biology
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 7 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 184 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf