Dataset Information

Expression data from isolated mouse lung endothelial cells

ABSTRACT: Exaggerated signaling by vascular endothelial growth factor (VEGF) A and its receptor, VEGFR2, in pathologies results in poor vessel function. Still, pharmacological suppression of VEGFA/VEGFR2 may aggravate disease. Delineating VEGFR2 signaling in vivo provides strategies for suppression of specific VEGFR2-induced pathways. Three VEGFR2 tyrosine residues (Y949, Y1212, Y1173) induce downstream signaling. Here, we show that knock-in of phenylalanine to create VEGFR2 Y1212F in C57Bl/6 and FVB mouse strains leads to loss of growth factor receptor bound (GRB)2- and phosphoinositide 3´kinase (PI3K)p85-signaling. C57Bl/6 Vegfr2Y1212F/Y1212F show reduced embryonic endothelial cell (EC) proliferation and partial lethality. FVB Vegfr2Y1212F/Y1212F show reduced postnatal EC proliferation. Reduced EC proliferation in Vegfr2Y1212F/Y1212F explants is rescued by c-Myc overexpression. We conclude that VEGFR2 Y1212 signaling induces activation of extracellular-signal regulated kinase (ERK)1/2 and Akt pathways required for c-Myc-dependent gene regulation, endothelial proliferation and vessel stability. We use microarray to determine the differences in gene expression in endothelial cells between WT or Vegfr2Y1212F/Y1212F mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE136085 | GEO | 2019/08/21

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here, we investigate the angiogenic functions of three separate nuclear genes that encode for mitochondrial proteins, including mitochondrial transcriptional factor (TFAM), respiratory complex IV component (COX10), and a mitochondrial redox protein thioredoxin 2 (TRX2), which are responsible for distinct mitochondrial functions. We aim to investigate if mitochondrial activities regulate common endothelial cell (EC) signaling pathways during angiogenesis. The silencing of Tfam, Cox10, or Trx2 in an in vitro 3D sprouting assay attenuates EC sprouting, which correlated with reduced EC proliferation but not with ROS generation or EC apoptosis. Mice with an inducible deletion of Tfam, Cox10, or Trx2 exhibit retarded retinal vessel growth without penetration into the deep plexi at early ages (P5-P12). The three mutant mice develop arteriovenous malformations (AVM) with microaneurysm formation in the microvessels at advanced ages (P12-P30); the hypovasculature and microaneurysm phenotypes resemble that of aged human retinas and human primitive retinal vascular abnormalities such as Coats’ disease, Leber’s military aneurysms and familial exudative vitreoretinopathy. Single-cell RNA-seq analyses of retinal ECs suggest that the three mutant mice have common EC clusters with reduced gene expressions in anion transporters, actin organization, extracellular matrix, and angiogenesis. These EC clusters also have increased gene expressions in endothelial-mesenchymal transition and arterial markers, correlating with enhanced TGFbR signaling in Tfam, Cox10, or Trx2-deficient mice. Importantly, pharmacological blockade by TGFbR inhibitors attenuated retinal vessel growth retardation and AVM formation in all three mutant mice. Our study demonstrates that mitochondrial dysfunction induces TGF-b receptor-mediated arteriovenous malformations and microaneurysm formation in mouse retinas, and provide a novel model and therapeutic intervention for human primitive retinal vascular abnormalities, which are characterized by retinal vascular malformations and are associated with many pathological complications such as diabetes and hypertension that can result in vision loss.

Dataset Information

Expression data from isolated mouse lung endothelial cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets