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

JCI Insight
Alexandra ArreolaJohn C Chappell

Abstract

Von Hippel-Lindau (VHL) gene mutations induce neural tissue hemangioblastomas, as well as highly vascularized clear cell renal cell carcinomas (ccRCCs). Pathological vessel remodeling arises from misregulation of HIFs and VEGF, among other genes. Variation in disease penetrance has long been recognized in relation to genotype. We show Vhl mutations also disrupt Notch signaling, causing mutation-specific vascular abnormalities, e.g., type 1 (null) vs. type 2B (murine G518A representing human R167Q). In conditional mutation retina vasculature, Vhl-null mutation (i.e., UBCCreER/+Vhlfl/fl) had little effect on initial vessel branching, but it severely reduced arterial and venous branching at later stages. Interestingly, this mutation accelerated arterial maturation, as observed in retina vessel morphology and aberrant α-smooth muscle actin localization, particularly in vascular pericytes. RNA sequencing analysis identified gene expression changes within several key pathways, including Notch and smooth muscle cell contractility. Notch inhibition failed to reverse later-stage branching defects but rescued the accelerated arterialization. Retinal vessels harboring the type 2B Vhl mutation (i.e., UBCCreER/+Vhlfl/2B) displayed stage-spe...Continue Reading

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Citations

May 9, 2019·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·Laura B PayneJohn C Chappell
Apr 16, 2019·Journal of Biological Engineering·Huaning Zhao, John C Chappell
Nov 15, 2018·Frontiers in Cardiovascular Medicine·Mark Sweeney, Gabor Foldes
Jan 8, 2019·The Journal of Clinical Investigation·John C ChappellW Kimryn Rathmell
Mar 23, 2018·Biomedicines·Jing Zhang, Qing Zhang
Aug 23, 2020·Journal of Clinical Medicine·Elisabetta PilottoEdoardo Midena
Mar 23, 2021·Current Tissue Microenvironment Reports·Laura Beth PayneJohn C Chappell

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Datasets Mentioned

BETA
GSE109102

Methods Mentioned

BETA
PCR
confocal microscopy
nucleotide exchange
RNA-Seq

Software Mentioned

Ensembl
Spliced Transcripts Alignment to a Reference ( STAR )
DAVID
DESeq2
featureCounts
ImageJ
GeneWiz

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