Angiopoietin-1 Is Required for Vortex Vein and Choriocapillaris Development in Mice

Abstract

BACKGROUND: The choroidal vasculature, including the choriocapillaris and vortex veins, is essential for providing nutrients to the metabolically demanding photoreceptors and retinal pigment epithelium. Choroidal vascular dysfunction leads to vision loss and is associated with age-related macular degeneration and the poorly understood pachychoroid diseases including central serous chorioretinopathy and polypoidal choroidal vasculopathy that are characterized by formation of dilated pachyvessels throughout the choroid. METHODS: Using neural crest-specific Angpt1 knockout mice, we show that Angiopoietin 1, a ligand of the endothelial receptor TEK (also known as Tie2) is essential for choriocapillaris development and vortex vein patterning. RESULTS: Lacking choroidal ANGPT1, neural crest-specific Angpt1 knockout eyes exhibited marked choriocapillaris attenuation and 50% reduction in number of vortex veins, with only 2 vortex veins present in the majority of eyes. Shortly after birth, dilated choroidal vessels resembling human pachyvessels were observed extending from the remaining vortex veins and displacing the choriocapillaris, leading to retinal pigment epithelium dysfunction and subretinal neovascularization similar to that seen in pachychoroid disease. CONCLUSIONS: Together, these findings identify a new role for ANGPT1 in ocular vascular development and demonstrate a clear link between vortex vein dysfunction, pachyvessel formation, and disease.

Non-endothelial expression of Endomucin in the mouse and human choroid

“…Non endothelial expression has been reported in skin (1), and in hematopoietic stem cells (26). In the mouse choroid, we and others have reported high EMCN expression that was attributed to endothelial cells (8-10). However, while EMCN expression is indeed high in choriocapillaries and other endothelial cells, at least some expression in these tissues originates in pericytes and fibroblasts.…”

“…Due to its near-ubiquitous expression by capillary endothelial cells and the commercial availability of high-quality antibodies, EMCN is commonly used as an endothelial marker in tissues of the eye, kidney, lung, and elsewhere (7)(8)(9)(10)(11)(12). However, its widespread use as a molecular marker has not translated to research focus, and beyond its role in VEGF signaling and neutrophil adhesion, EMCN remains poorly understood (13).…”

One-year visual and anatomical outcomes of intravitreal faricimab injection for neovascular age-related macular degeneration after prior brolucizumab treatment

“…The biological significance of Ang-2 has been experimentally demonstrated in terms of the effect of Tie2 activation on choroidal ischemia 38 . Additionally, knockout mice of Angptl1 in choroidal vessels have been shown to develop “pachychoroid (thick choroid)” 39 . Therefore, it is conceivable that Ang2 inhibition can improve choroidal circulation and ameliorate the morbidity caused by thickened choroidal thickness, further studies are needed to envelope the detailed mechanism.…”

Visual and Anatomical Outcomes After Initial Intravitreal Faricimab Injection for Neovascular Age-Related Macular Degeneration in Patients with Prior Treatment History

“…Previous studies found that VEGF concentrations in the aqueous humor were lower in eyes with pachychoroid neovascularization than in those with drusen-associated MNV [ 25 , 26 ], whereas Ang-2 is elevated in eyes with pachychoroid features [ 26 ]. Moreover, knockout of Ang-1 in mice leads to a pachychoroid phenotype, indicating the role of angiopoietins in choroidal remodeling [ 27 ]. Taken together, our results support the hypothesis that dual Ang-2/VEGF-A inhibition potentiates choroidal vascular remodeling, which might give better results for Asian patients with nAMD, especially those associated with the pachychoroid phenotype.…”