Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization

Author:

Ali Zaheer1,Mukwaya Anthony2,Biesemeier Antje3,Ntzouni Maria4,Ramsköld Daniel5,Giatrellis Sarantis5,Mammadzada Parviz6,Cao Renhai7,Lennikov Anton2,Marass Michele8,Gerri Claudia8,Hildesjö Camilla9,Taylor Michael10,Deng Qiaolin11,Peebo Beatrice2,del Peso Luis1213,Kvanta Anders6,Sandberg Rickard5,Schraermeyer Ulrich3,Andre Helder6,Steffensen John F.14,Lagali Neil2,Cao Yihai7,Kele Julianna11,Jensen Lasse Dahl1

Affiliation:

1. From the Division of Cardiovascular Medicine, Department of Medical and Health Sciences (Z.A., L.D.J.), Linkoping University, Sweden

2. Division of Ophthalmology, Department of Clinical and Experimental Medicine (A.M., A.L., B.P., N.L.), Linkoping University, Sweden

3. Experimental Vitreoretinal Surgery, Center for Ophthalmology, University of Tuebingen, Germany (A.B., U.S.)

4. Electronmicroscopy and Histology Laboratory, Faculty of Medicine (M.N.), Linkoping University, Sweden

5. Department of Cell and Molecular Biology (D.R., S.G., R.S.), Karolinska Institutet, Stockholm, Sweden

6. Department of Clinical Neuroscience, Section for Ophthalmology and Vision, St. Erik Eye Hospital (P.M., A.K., H.A.), Karolinska Institutet, Stockholm, Sweden

7. Department of Microbiology, Tumor and Cell Biology (R.C., Y.C.), Karolinska Institutet, Stockholm, Sweden

8. Department of Developmental Genetics, Max Planck Institute for Lung and Heart Research, Bad Nauheim, Germany (M.M., C.G.)

9. Division of Surgery, Orthopedics and Oncology, Department for Clinical and Experimental Medicine (C.H.), Linkoping University, Sweden

10. Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison (M.T.)

11. Department of Physiology and Pharmacology (Q.D., J.K.), Karolinska Institutet, Stockholm, Sweden

12. Department of Biochemistry, Universidad Autónoma de Madrid, Spain (L.d.P.)

13. Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain (L.d.P.)

14. Marine Biological Section, Biological Institute, University of Copenhagen, Helsingor, Denmark (J.F.S.).

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. Visual Overview— An online visual overview is available for this article.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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