| 1. |
- Ali, Zaheer, et al.
(författare)
-
Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization
- 2019
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 39:7, s. 1402-1418
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 2. |
- Mammadzada, Parviz, 1988-
(författare)
-
Investigation of potential prognostic and therapeutic genes in pathologic neovascularization of the retina
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pathologic angiogenesis of the retina is a hallmark of frequent blinding conditions among the elderly, such as proliferative diabetic retinopathy (PDR) and neovascular age-related macular degeneration (nAMD). The underlying mechanisms are complex. Currently, the approved therapies consist of intraocular injections of antivascular endothelial growth factor (VEGF) agents, laser treatments, and intraocular surgeries to cope with the complications, such as intravitreal bleeding. Although these therapies are the cornerstone of ophthalmological care for the patients, they are far from perfect. There is a clear need for understanding the intricate regulatory mechanisms of different retinal angiogenic conditions and find novel prognostic and therapeutic tools. Investigation of angiogenesis at the gene regulation level grants the possibility of studying angiogenesis within the tissue of origin, finding biomarkers of disease progression, and offering novel targets and therapy modalities, such as gene therapy agents. This thesis provides further insight into the complexity and heterogeneity of retinal angiogenesis by analyzing human endothelial cells from retinal and choroidal vasculature. Furthermore, we show the biomarker potential of specific microRNAs in PDR progression, focusing on recurrent vitreous hemorrhage. Moreover, we show that hypoxia-inducible factor (HIF)-1α, a master regulator of angiogenesis, is upregulated in retinal pigment epithelium (RPE) in hypoxia. HIFs pathologic upregulation can be mitigated by overexpression of prolyl hydroxylase domain (PHD)2, a prominent HIF regulatory protein. In vitro and in vivo experiments with overexpression of PHD2 protein diminished hypoxia-induced molecular and cellular angiogenesis. Gene therapy experiments in the choroidal neovascularization (CNV) mouse model with PHD2 significantly reduced laser-induced CNV lesions. Therefore, we provide a candidate molecule for anti-HIF gene therapy for sustained and balanced inhibition of retinal angiogenic conditions.
|
|
