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Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
Univ Tubingen, Germany.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
Vise andre og tillknytning
2019 (engelsk)Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, nr 7, s. 1402-1418Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Lippincott Williams & Wilkins, 2019. Vol. 39, nr 7, s. 1402-1418
Emneord [en]
choroidal neovascularization; hypoxia; intussusception; macular degeneration; zebrafish
HSV kategori
Identifikatorer
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
Merknad

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

Tilgjengelig fra: 2019-07-20 Laget: 2019-07-20 Sist oppdatert: 2019-08-22bibliografisk kontrollert

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Ali, ZaheerMukwaya, AnthonnyNtzouni, MariaLennikov, AntonHildesjö, CamillaPeebo, BeatriceLagali, NeilJensen, Lasse
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Arteriosclerosis, Thrombosis and Vascular Biology

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