Deletion of Endothelial Transforming Growth Factor–β Signaling Leads to Choroidal Neovascularization

Abstract

The molecular pathogenesis of choroidal neovascularization (CNV), an angiogenic process that critically contributes to vision loss in age-related macular degeneration, is unclear. Herein, we analyzed the role of transforming growth factor (TGF)-β signaling for CNV formation by generating a series of mutant mouse models with induced conditional deletion of TGF-β signaling in the entire eye, the retinal pigment epithelium (RPE), or the vascular endothelium. Deletion of TGF-β signaling in the eye caused CNV, irrespectively if it was ablated in newborn or 3-week-old mice. Areas of CNV showed photoreceptor degeneration, multilayered RPE, basal lamina deposits, and accumulations of monocytes/macrophages. The changes progressed, leading to marked structural and functional alterations of the retina. Although the specific deletion of TGF-β signaling in the RPE caused no obvious changes, specific deletion in vascular endothelial cells caused CNV and a phenotype similar to that observed after the deletion in the entire eye. We conclude that impairment of TGF-β signaling in the vascular endothelium of the eye is sufficient to trigger CNV formation. Our findings highlight the importance of TGF-β signaling as a key player in the development of ocular neovascularization and indicate a fundamental role of TGF-β signaling in the pathogenesis of age-related macular degeneration.

SWATH-MS Proteomic Analysis of Oxygen-Induced Retinopathy Reveals Novel Potential Therapeutic Targets

“…This is in accordance with previous studies showing TGF-b1 upregulation in OIR. 60 Interestingly, conditional ocular deletions of TGF-b signaling results in pronounced structural changes of retinal capillaries and a phenotype similar to human DR. 61,62 The upstream regulator analysis identified Mkl2 and FIGURE 8. Selection of upregulated proteins at P42 OIR.…”

The Role of Inflammation in Age-Related Macular Degeneration

“…TGF-β plays a vital role in the formation and development of CNV by Smad2/3-VEGF/TNF-α signaling pathway in wet AMD [88]. Interestingly, other studies indicated that deficient of TGF-β signaling leads to retinal degeneration and exacerbates CNV [89,90]. Furthermore, TGF-β promotes the EMT of RPE cells, induces subretinal fibrosis and production of IL-6 [60].…”

The Controversial Role of TGF-β in Neovascular Age-Related Macular Degeneration Pathogenesis

“…Specularly, in the developing eyes of mice lacking Tgf-β2 (Tgfb2 −/− ), persistent vitreous vessels could be detected [ 50 ]. Moreover, the induced conditional deletion of TβRII in the entire eye or in the vascular endothelium of the eye, but not in RPE, caused an increased retinal expression of VEGF-A, the development of CNV, and the induction of other phenotypic characteristics of nAMD [ 71 ]. In a mouse model of oxygen-induced retinopathy, intraperitoneally injected human placental amniotic membrane-derived mesenchymal stem cells migrated into the retina and suppressed excessive neovascularization by TGF-β1 expression [ 72 ].…”