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 20 publications

(17 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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“…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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“…In each of these situations, maintaining adequate tissue perfusion following the primary insult remains a challenge and could involve targeting pericytes. We recently found that disrupting oxygen‐sensing mechanisms via induced genetic Vhl mutations accelerated vessel maturation and specifically caused pericytes within developing retinal vasculature to ectopically express αSMA . Taken together with previous studies, it is intriguing to speculate that the hypoxic conditions within several of the aforementioned disease states might not only antagonize pericyte constriction mechanisms but also cause an aberrant increase in the expression of αSMA and other contractile machinery proteins.…”

Section: Pericytes In the Transition From Angiogenic Sprouting To Vesmentioning

confidence: 78%

The pericyte microenvironment during vascular development

et al. 2019

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Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.

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

Cited by 20 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

Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

The pericyte microenvironment during vascular development

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