Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII

Chu, Maoping; Li, Taotao; Shen, Bin; Cao, Xudong; Zhong, Haoyu; Zhang, Luqing; Zhou, Fei; Ma, Wenjuan; Jiang, Haijuan; Liu, Zhengzheng; Dong, Ningzheng; Xu, Ying; Zhao, Yun; Xu, Guoqiang; Lu, Peirong; Luo, Jincai; Wu, Qingyu; Alitalo, Kari; Koh, Gou Young; Adams, Ralf H.; He, Yulong

doi:10.7554/elife.21032

Cited by 56 publications

(79 citation statements)

References 38 publications

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“…36,37 In addition to its role in SC, TEK signaling plays a key role in retinal angiogenesis, although the role of ANGPT1 is poorly described. 38,39 Outside of the eye, Angpt1 knockout mice have defects in vascular remodeling, 9 and ANGPT1 overexpression leads to dermal capillary widening. 40,41 In the retina, Angpt1 is expressed by neurons adjacent to the superficial and intermediate vascular layers, although not in RGCs.…”

Section: Angpt1 Wb Mice Are a Model Of High-pressure Open-angle Glaucomamentioning

confidence: 99%

Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma

Thomson

Grannonico

Liu

et al. 2020

Trans. Vis. Sci. Tech.

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A leading cause of blindness worldwide, glaucoma is often caused by elevated intraocular pressure (IOP) due to impaired aqueous humor outflow from the anterior chamber through Schlemm's canal (SC) and the trabecular meshwork. Despite the large clinical burden, glaucoma research and drug development are hindered by a limited selection of preclinical models that accurately recapitulate human disease. Here, we propose that Angpt1 conditional knockout mice may provide one such model. Angiopoietin/TEK (ANGPT/TEK) signaling is crucial for SC formation and integrity in mice and humans, and mice lacking TEK or its ligand ANGPT1 develop a hypomorphic SC insufficient for normal aqueous humor outflow. Methods: We used a comprehensive histology and physiology approach to characterize the glaucoma phenotype of Angpt1 inducible knockout mice, especially focusing on retina morphology and function. Results: Angpt1 deletion resulted in persistent ocular hypertension beginning in the first month after birth and leading to decreased visual acuity with age due to glaucomatous neuropathy. In the neural retina, we identified marked and specific loss of the retinal ganglion cells, whereas other retinal neurons exhibited largely normal morphology and patterning. Electroretinogram recordings demonstrated reduced scotopic threshold response, further indicating loss of retinal ganglion cell function. Conclusions: These findings highlight the potential of Angpt1 conditional knockout mice as a valuable new glaucoma model. Translational Relevance: Currently, few reliable, rapid-onset genetic glaucoma models are available, and Angpt1 knockout mice will provide an additional tool for studies of IOP-induced neural damage, mechanisms of disease progression, and novel treatment strategies.

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Section: Angpt1 Wb Mice Are a Model Of High-pressure Open-angle Glaucomamentioning

confidence: 99%

Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma

Thomson

Grannonico

Liu

et al. 2020

Trans. Vis. Sci. Tech.

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“…Vertebrates encode three Akt isoforms: Akt1, Akt2, and Akt3 and these unique gene products are highly homologous between species. The Akt-signaling module is implicated in arteriogenesis by exerting an inhibitory influence on Raf-Erk-signaling (Ren et al, 2010) or in venogenesis via phosphorylation of the COUP TFII, a key driver of venous fate (Chu et al, 2016). However mice globally lacking Akt-1, the main isoform expressed in endothelial cells, are viable, smaller in size, with reduced angiogenesis in the placenta, retina and limbs (Ackah et al, 2005;Ha et al, 2019;Schleicher et al, 2009;Yang et al, 2003) whereas the conditional loss of Akt-1 in the endothelium demonstrates reduced post-natal arteriogenesis and sprouting of retinal (Lee et al, 2014) and coronary vessels (Kerr et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Akt is required for artery formation during embryonic vascular development

Zhou

Ristori

et al. 2020

Preprint

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One of the first events in the development of the cardiovascular system is morphogenesis of the main embryonic artery, the dorsal aorta (DA). The DA forms via a conserved genetic process mediated by the migration, specification, and organization of endothelial progenitor cells into a distinct arterial lineage and vessel type. Several angiogenic factors activate different signaling pathways to control DA formation, however the physiological relevance of distinct kinases in this complex process remains unclear. Here, we identify the role of Akt during early vascular development by generating mutant zebrafish lines that lack expression of akt isoforms. Live cell imaging coupled with single cell RNA sequencing of akt mutants reveal that Akt is required for proper development of the DA by sustaining arterial cell progenitor specification and segregation. Mechanistically, inhibition of active FOXO in akt mutants rescues impaired arterial development but not the expression of arterial markers, whereas Notch activation rescues arterial marker expression. Our work suggests that Akt activity is critical for early artery development, in part via FOXO and Notch-mediated regulation.

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“…Although angiogenesis has been studied extensively (Bentley et al, 2014;Costa et al, 2016;Hellström et al, 2007;Jakobsson et al, 2010;Pitulescu et al, 2017;Sawamiphak et al, 2010;Tamagnone and Mazzone, 2011;Tammela et al, 2011), much less is known about developmental remodeling. Nonetheless, it is well recognized that developmental remodeling involves multiple regulated processes, including recruitment of mural cells, regulation of vascular calibers, and pruning (regression) of excess microvessels (Arreola et al, 2018;Cheng et al, 2012;Chu et al, 2016;Ehling et al, 2013;Ishida et al, 2003;Korn et al, 2014;Phng et al, 2009;Scott et al, 2010;Simonavicius et al, 2012;Watson et al, 2016;Zaitoun et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Developmental vascular pruning in neonatal mouse retinas is programmed in the astrocytic oxygen sensing mechanism

Duan

Fong

2019

Development

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Vascular pruning is crucial for normal development, but its underlying mechanisms are poorly understood. Here, we report that retinal vascular pruning is controlled by the oxygen-sensing mechanism in local astrocytes. Oxygen sensing is mediated by prolyl hydroxylase domain proteins (PHDs), which use O 2 as a substrate to hydroxylate specific prolyl residues on hypoxia inducible factor (HIF)-α proteins, labeling them for polyubiquitylation and proteasomal degradation. In neonatal mice, astrocytic PHD2 deficiency led to elevated HIF-2α protein levels, expanded retinal astrocyte population and defective vascular pruning. Although astrocytic VEGF-A was also increased, anti-VEGF failed to rescue vascular pruning. However, stimulation of retinal astrocytic growth by intravitreal delivery of PDGF-A was sufficient to block retinal vascular pruning in wild-type mice. We propose that in normal development, oxygen from nascent retinal vasculature triggers PHD2-dependent HIF-2α degradation in nearby astrocytic precursors, thus limiting their further growth by driving them to differentiate into non-proliferative mature astrocytes. The physiological limit of retinal capillary density may be set by astrocytes available to support their survival, with excess capillaries destined for regression. This article has an associated 'The people behind the papers' interview.

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Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII

Cited by 56 publications

References 38 publications

Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma

Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma

Akt is required for artery formation during embryonic vascular development

Developmental vascular pruning in neonatal mouse retinas is programmed in the astrocytic oxygen sensing mechanism

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