Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization

Zaheer Ali; Anthony Mukwaya; Antje Biesemeier; Maria Ntzouni; Daniel Ramsköld; Sarantis Giatrellis; Parviz Mammadzada; Renhai Cao; Anton Lennikov; Michele Marass; Claudia Gerri; Camilla Hildesjö; Michael Taylor; Qiaolin Deng; Beatrice Peebo; Luis del Peso; Anders Kvanta; Rickard Sandberg; Ulrich Schraermeyer; Helder Andre; John F. Steffensen; Neil Lagali; Yihai Cao; Julianna Kele; Lasse Dahl Jensen

doi:10.1161/ATVBAHA.118.312190

Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization

Zaheer Ali, Anthony Mukwaya, Antje Biesemeier, Maria Ntzouni, Daniel Ramsköld, Sarantis Giatrellis, Parviz Mammadzada, Renhai Cao, Anton Lennikov, Michele Marass, Claudia Gerri, Camilla Hildesjö, Michael Taylor, Qiaolin Deng, Beatrice Peebo, Luis del Peso, Anders Kvanta, Rickard Sandberg, Ulrich Schraermeyer, Helder AndreJohn F. Steffensen, Neil Lagali, Yihai Cao, Julianna Kele, Lasse Dahl Jensen

Marine Biological Section

6 Citationer (Scopus)

12 Downloads (Pure)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Arteriosclerosis, Thrombosis, and Vascular Biology
Vol/bind	39
Udgave nummer	7
Sider (fra-til)	1402-1418
ISSN	1079-5642
DOI	https://doi.org/10.1161/ATVBAHA.118.312190
Status	Udgivet - 2019

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10.1161/ATVBAHA.118.312190Licens: CC BY

Intussusceptive Vascular Remodeling Precedes Pathological NeovascularizationForlagets udgivne version, 1,25 MBLicens: CC BY

Citationsformater

Ali, Z., Mukwaya, A., Biesemeier, A., Ntzouni, M., Ramsköld, D., Giatrellis, S., Mammadzada, P., Cao, R., Lennikov, A., Marass, M., Gerri, C., Hildesjö, C., Taylor, M., Deng, Q., Peebo, B., del Peso, L., Kvanta, A., Sandberg, R., Schraermeyer, U., ... Jensen, L. D. (2019). Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(7), 1402-1418. https://doi.org/10.1161/ATVBAHA.118.312190

Ali, Z, Mukwaya, A, Biesemeier, A, Ntzouni, M, Ramsköld, D, Giatrellis, S, Mammadzada, P, Cao, R, Lennikov, A, Marass, M, Gerri, C, Hildesjö, C, Taylor, M, Deng, Q, Peebo, B, del Peso, L, Kvanta, A, Sandberg, R, Schraermeyer, U, Andre, H, Steffensen, JF, Lagali, N, Cao, Y, Kele, J & Jensen, LD 2019, 'Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization', Arteriosclerosis, Thrombosis, and Vascular Biology, bind 39, nr. 7, s. 1402-1418. https://doi.org/10.1161/ATVBAHA.118.312190

@article{d709c0a5747347b68db27b5d9070e772,

title = "Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization",

abstract = "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.",

keywords = "choroidal neovascularization, hypoxia, intussusception, macular degeneration, zebrafish",

author = "Zaheer Ali and Anthony Mukwaya and Antje Biesemeier and Maria Ntzouni and Daniel Ramsk{\"o}ld and Sarantis Giatrellis and Parviz Mammadzada and Renhai Cao and Anton Lennikov and Michele Marass and Claudia Gerri and Camilla Hildesj{\"o} and Michael Taylor and Qiaolin Deng and Beatrice Peebo and {del Peso}, Luis and Anders Kvanta and Rickard Sandberg and Ulrich Schraermeyer and Helder Andre and Steffensen, {John F.} and Neil Lagali and Yihai Cao and Julianna Kele and Jensen, {Lasse Dahl}",

year = "2019",

doi = "10.1161/ATVBAHA.118.312190",

language = "English",

volume = "39",

pages = "1402--1418",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams & Wilkins",

number = "7",

}

TY - JOUR

T1 - Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization

AU - Ali, Zaheer

AU - Mukwaya, Anthony

AU - Biesemeier, Antje

AU - Ntzouni, Maria

AU - Ramsköld, Daniel

AU - Giatrellis, Sarantis

AU - Mammadzada, Parviz

AU - Cao, Renhai

AU - Lennikov, Anton

AU - Marass, Michele

AU - Gerri, Claudia

AU - Hildesjö, Camilla

AU - Taylor, Michael

AU - Deng, Qiaolin

AU - Peebo, Beatrice

AU - del Peso, Luis

AU - Kvanta, Anders

AU - Sandberg, Rickard

AU - Schraermeyer, Ulrich

AU - Andre, Helder

AU - Steffensen, John F.

AU - Lagali, Neil

AU - Cao, Yihai

AU - Kele, Julianna

AU - Jensen, Lasse Dahl

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - choroidal neovascularization

KW - hypoxia

KW - intussusception

KW - macular degeneration

KW - zebrafish

U2 - 10.1161/ATVBAHA.118.312190

DO - 10.1161/ATVBAHA.118.312190

M3 - Journal article

C2 - 31242036

SN - 1079-5642

VL - 39

SP - 1402

EP - 1418

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 7

ER -

Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization

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