Synchronized tissue-scale vasculogenesis and ubiquitous lateral sprouting underlie the unique architecture of the choriocapillaris

Ali, Zaheer; Cui, Dongmei; Yang, Yunlong; Tracey‐White, Dhani; Rodriguez, Gabriela Vazquez; Moosajee, Mariya; Ju, Rong; Li, Xuri; Cao, Yihai; Jensen, Lasse

doi:10.1016/j.ydbio.2019.02.002

Cited by 10 publications

(11 citation statements)

References 39 publications

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“…While the role of ANGPT1 in choroid development remains little understood, numerous studies have reported the essential role for RPE-derived VEGF in choriocapillaris development and function. 1,2,16,17 Vegfa is also expressed in the choroidal stroma (Figure 1C) and to determine if choroidal VEGF, like ANGPT1, is necessary for choriocapillaris and vortex vein development, we generated neural crest-specific Vegfa deleted mice using Wnt1 -Cre. Vegfa ΔNC mice were born alive but died immediately after birth exhibiting previously described craniofacial defects 52 and dilated intestines filled with air (Figure 8A).…”

Section: Resultsmentioning

confidence: 99%

“…These then lumenize to form a primitive choriocapillaris through vasculogenesis by E11.5 in mice. 8,9,17,39,78 This structure expands through angiogenic sprouting, increasing in density and undergoing flow-mediated remodeling as the mature choriocapillaris is formed. 8,9,17,78 Angiopoietin signaling is not required for vasculogenesis, and outside of the eye, mice lacking angiopoietin 1 or TEK from birth are viable until E10.5 to E12.5, when the embryonic vasculature fails to develop beyond the primary capillary plexus.…”

Section: Discussionmentioning

confidence: 99%

“…8,9,17,39,78 This structure expands through angiogenic sprouting, increasing in density and undergoing flow-mediated remodeling as the mature choriocapillaris is formed. 8,9,17,78 Angiopoietin signaling is not required for vasculogenesis, and outside of the eye, mice lacking angiopoietin 1 or TEK from birth are viable until E10.5 to E12.5, when the embryonic vasculature fails to develop beyond the primary capillary plexus. 22,40,79 Our data suggest a similar mechanism in the choriocapillaris, choroidal vasculature is present in Angpt1 ΔNC mice at E12.5 and attenuation is apparent only after the later phases of choriocapillaris angiogenesis and remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the well-described role of VEGF (vascular endothelial growth factor) signaling in choriocapillaris development and maintenance, 1,2,[16][17][18] the angiopoietin receptor TEK is expressed by the choriocapillaris endothelium 19 and its dominant ligand ANGPT1 has been reported in uveal tissues. 20,21 In development, the embryonic timeline of choroid and choriocapillaris formation has hindered studies using embryonically lethal Angpt1 or Tek knockout models that die in mid gestation.…”

Section: See Cover Imagementioning

confidence: 99%

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

Liu

Lavine

Fawzi

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: See Cover Imagementioning

confidence: 99%

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

Liu

Lavine

Fawzi

et al. 2022

ATVB

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“…Retinal vasculature development after birth in mice provides a unique opportunity to study developmental angiogenesis. Normal mouse retinal vasculature growth is well documented, and drugs can inhibit this growth [27][28][29].…”

Section: Subcutaneous Calcitriol Treatment Does Not Adversely Affect Adult Mouse Retinal Structures or Superficial Retinal Vasculature Dementioning

confidence: 99%

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2020

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Aberrant ocular angiogenesis can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, may lack efficacy and are associated with poor patient compliance and tachyphylaxis. Vitamin D has de novo anti-angiogenic properties. Here, our aim was to validate the ocular anti-angiogenic activity of biologically active vitamin D, calcitriol, and selected vitamin D analogue, 22-oxacalcitriol. Calcitriol induced a significant reduction in ex vivo mouse choroidal fragment sprouting. Viability studies in a human RPE cell line suggested non-calcemic vitamin D analogues including 22-oxacalcitriol have less offtarget anti-proliferative activity compared to calcitriol and other analogues. Thereafter, the anti-angiogenic activity of 22-oxacalcitriol was demonstrated in an ex vivo mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was found to be anti-angiogenic, inducing a dose-dependent reduction in choriocapillaris development. Subcutaneously administered calcitriol failed to attenuate mouse retinal vasculature development. However, calcitriol and 22-oxacalcitriol administered intraperitoneally, significantly attenuated lesion volume in the laser-induced choroidal neovascularisation mouse model. In summary, calcitriol and 22-oxacalcitriol attenuate ex vivo and in vivo choroidal vasculature angiogenesis. Therefore, vitamin D may have potential as an interventional treatment for ophthalmic neovascular indications. InTRoduCTIonPathological neovascularisation of ocular blood vessels can promote vision loss in leading causes of blindness including neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy. Worldwide, 8.7% of blindness results from AMD. nAMD accounts for only 10% of AMD cases but greater than 80% of poor visual acuity cases [1][2][3][4]. Rapid vision loss in nAMD is driven by pathological choroidal vasculature angiogenesis. This pathological vasculature can be deficient in tight junctions, leak plasma or blood, cause scarring, project through the Bruch's membrane, cause retinal pigmented epithelium (RPE) detachment and disrupt normal perfusion of the retina [5][6][7]. Worldwide 382 million people suffer from www.oncotarget.com

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