Von Hippel-Lindau mutations disrupt vascular patterning and maturation via Notch

Arreola, Alexandra; Payne, Laura Beth; Julian, Morgan H.; Cubas, Aguirre A. de; Daniels, Anthony B.; Taylor, Sarah; Zhao, Huaning; Darden, Jordan; Bautch, Victoria L.; Rathmell, W. Kimryn; Chappell, John C.

doi:10.1172/jci.insight.92193

Cited by 21 publications

(19 citation statements)

References 53 publications

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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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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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“…Paradoxically, therefore, high Hif does not induce RCH, but instead inhibits retinal angiogenesis in the murine Vhl -/retina. Deleting Vhl in all retinal cells and vascular endothelial cells using UBC-Cre ER also suppresses retinal angiogenesis (22). Deleting Vhl in specific retinal cell types, such as amacrine or horizontal interneurons (23), rods (24), cones (25), or retinal pigment epithelium (RPE) cells (26), also does not induce RCH.…”

mentioning

confidence: 99%

Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma

Wei¹,

Ren²,

Kong³

et al. 2019

JCI Insight

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vascular plexuses, including the superficial vascular plexus (SVP) in the nerve fiber layer, deep vascular plexus (DVP) in the outer plexiform layer (OPL), and intermediate vascular plexus (IVP) in the inner plexiform layer (16).The origin of the true tumorigenic cell type in RCH and RAP is controversial. This reflects the dearth of human samples available for histopathological analyses, limiting the vast majority of studies to observations in intact human eyes. In RCH, early work referred to an astrocytic component (17). More recently, but with only 3 cases, 2 groups reported that glial fibrillary acidic protein-positive (GFAP + ) glial cells contribute to human RCH (18,19). Thus, the cell of origin of human RCH needs further investigation.Deleting Vhl in murine retina delays regression of hyaloid vessels and inhibits retinal angiogenesis, which depend on the associated high levels of 21). Paradoxically, therefore, high Hif does not induce RCH, but instead inhibits retinal angiogenesis in the murine Vhl -/retina. Deleting Vhl in all retinal cells and vascular endothelial cells using UBC-Cre ER also suppresses retinal angiogenesis (22). Deleting Vhl in specific retinal cell types, such as amacrine or horizontal interneurons (23), rods (24), cones (25), or retinal pigment epithelium (RPE) cells (26), also does not induce RCH. Although removing Vhl in murine hemangioblasts using stem cell leukemia-Cre ER (Scl-Cre ER ) triggered some features of early-stage RCH, including dilated tortuous vessels, vascular leakage, and foamy stromal cell clusters, histologically it did not cause any neovascularization or hemangioblastoma structures in the retina (27). Thus, it remains unclear why the Vhl -/retina lacks vascular overgrowth and RCH. One possibility is that inhibitors interfere with Hif activity. Indeed, an SNP microarray study implicated several cell cycle genes in the pathogenesis of hemangioblastoma, including the retinoblastoma repressor (Rb1) (28). Inactivating Vhl plus additional tumor suppressors (Rb1 and tumor protein p53; Tp53) can induce CCRCC (29). However, inhibitors that block angiogenesis in the Vhl -/murine retina are unknown.In addition to angiogenesis, autophagy is important for hypoxia adaptation because it captures and degrades intracellular components to sustain metabolism and homeostasis (30). Hypoxia-induced autophagy requires the constitutive expression of beclin 1 (Becn1) and autophagy related 5 (Atg5) and the Hif1-dependent expression of Bnip3/Bnip3L (30,31). Autophagy has been observed in human RCH (32), but its role in the Vhl -/murine retina is unclear.Retinoblastoma is the most common pediatric intraocular tumor. Rb1 regulates cell cycle, cell death, and many other cellular processes in part by inhibiting the E2f transcription factors (33). Loss of Rb1 and its relative Rbl1 (also called p107) in the retina causes mouse retinoblastoma (34-36). In the Rb1/Rbl1-null retina, all differentiating cells divide ectopically, excitatory neurons (ganglion cells, bipolar cells, rods, and cones) underg...

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“…Retinal vessels of type 2B Vhl-mutant animals displayed hallmarks of an accelerated progression toward an arterial phenotype, including ectopic expression of vascular smooth muscle contractility proteins in microvascular pericytes (Figure 3 and ref. 98). We further found that both types 1 and 2B genetic mutations resulted in abnormal angiogenic remodeling and changes in stage-specific vascular density (Figure 3 and ref.…”

Section: Hlrcc: An Illustration Of Metabolically Driven Hereditary Kimentioning

confidence: 55%

Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

Chappell¹,

Payne²,

Rathmell³

2019

Journal of Clinical Investigation

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Von Hippel-Lindau mutations disrupt vascular patterning and maturation via Notch

Cited by 21 publications

References 53 publications

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

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

Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma

Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

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