Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis

Walker, Andrew M N; Warmke, Nele; Mercer, Ben; Watt, Nicole T.; Mughal, Romana; Smith, Jessica; Galloway, S; Haywood, Natalie; Soomro, Taha; Griffin, Kathryn J.; Wheatcroft, Stephen; Yuldasheva, Nadira; Beech, David J; Carmeliet, Peter; Kearney, Mark T.; Cubbon, Richard M

doi:10.1210/endocr/bqab104

Cited by 22 publications

(20 citation statements)

References 52 publications

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“…Park and colleagues also confirm that endothelial FoxO1, but not pericyte-derived ANGPT1, contributes to the vascular dysfunction caused by pericyte loss, suggesting other pericyte derived factors are important ( 41 ). Our recent work has also shown interactions between endothelial insulin receptors and VEGF signaling in endothelial cells during angiogenesis, illustrating a broader role of insulin signaling in vascular remodeling ( 42 ). Hence, insulin signaling appears to play a complex role in angiogenesis, and further work will be required to address the uncertainties described above.…”

Section: Discussionmentioning

confidence: 70%

Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling

et al. 2021

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Pericytes regulate vascular development, stability and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFR β-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited peri-venous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in peri-venous and peri-arterial plexi and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the peri-venous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease.

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Section: Discussionmentioning

confidence: 70%

Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling

et al. 2021

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“…However, the most strikingly differentially expressed gene sets in AD are involved in angiogenesis and vascular homeostasis. VEGF/VEGFR and insulin signalling pathways 54 in EC and EGF/EGFR signalling in EC and PC were downregulated with AD 55 and negatively correlated with Aβ pathology, despite upregulation of other genes (e.g. HIF1A) associated with pro-angiogenic regulation 28 .…”

Section: Discussionmentioning

confidence: 94%

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer’s disease

Tsartsalis

Fancy

Smith

et al. 2021

Preprint

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Brain perfusion and normal blood brain barrier integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains to characterise pathological transcriptional signatures. We found that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. EC transcriptional signatures identified mechanisms for impaired β-amyloid clearance. Evidence for immune activation was found with upregulation of interferon signalling genes in EC and in pericytes (PC). Transcriptional signatures suggested dysregulation of vascular homeostasis and angiogenesis with upregulation of pro-angiogenic signals (HIF1A) and metabolism in EC, but downregulation of homeostatic growth factor pathways (VEGF, EGF, insulin) in EC and PC and of extracellular matrix genes in fibroblasts (FB). Our genomic dissection of vascular cell risk gene enrichment suggests a potentially causal role for EC and defines transcriptional signatures associated with microvascular dysfunction in AD.

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“…Specifically, in the degenerated meniscus, CXCL8 was produced by macrophages/monocytes, neutrophils, and DC; and its receptor SDC2 was expressed on the chondrocytes and the pericyte like cells. Many cell types produced CALM1/2 that binds to the endothelial cells and promotes the growth of the endothelium 37 . We also identified degeneration group enhanced crosstalk mediated by: class I HLA → APLP2 interactions, TNF superfamily interactions (TNF, TNFSF10 → VSIR, TNFRSF1A/B), and TGF superfamily interactions (INHBA→ENG).…”

Section: Resultsmentioning

confidence: 99%

Depiction of cell atlas and analysis of microenvironment alterations in human meniscus degeneration using single-cell transcriptomic

Chen

Yang

et al. 2022

Preprint

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BackgroundMusculoskeletal tissue degeneration impairs the life quality and function of many people. Meniscus degeneration is a major origin of knee osteoarthritis and a common threat to athletic ability, but its cellular mechanism remains elusive.MethodsWe built a cell atlas of healthy/degenerated human meniscus using scRNA-seq to investigate meniscal microenvironment homeostasis and its changes in the degeneration process and verified findings with immunofluorescent imaging.ResultsWe identified and localized cell types in inner and outer meniscus, found new chondrocyte subtypes contributing to degeneration, and revealed how cellular compositions, functions, and interactions participated in degeneration.We found that ECM disassembly, angiogenesis, and inflammation form a positive feedback loop driving the degeneration. Comparison of cellular interactions between different degenerative states identified each cell type’s functions in the loop.ConclusionsThe study revealed changes in the meniscal microenvironment during degeneration and discovered new cell subtypes as potential therapeutic targets. The observed mechanism could also be a general model for other joint degenerations.FundingThe National Natural Science Foundation of China (81972123, 82172508, 62050178, 61721003) and the National Key Research and Development Program of China (2021YFF1200901).

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Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis

Cited by 22 publications

References 52 publications

Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling

Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer’s disease

Depiction of cell atlas and analysis of microenvironment alterations in human meniscus degeneration using single-cell transcriptomic

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