NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy

Nature Communications
Alexandre DubracAnne Eichmann

Abstract

Pericytes are mural cells that surround capillaries and control angiogenesis and capillary barrier function. During sprouting angiogenesis, endothelial cell-derived platelet-derived growth factor-B (PDGF-B) regulates pericyte proliferation and migration via the platelet-derived growth factor receptor-β (PDGFRβ). PDGF-B overexpression has been associated with proliferative retinopathy, but the underlying mechanisms remain poorly understood. Here we show that abnormal, α-SMA-expressing pericytes cover angiogenic sprouts and pathological neovascular tufts (NVTs) in a mouse model of oxygen-induced retinopathy. Genetic lineage tracing demonstrates that pericytes acquire α-SMA expression during NVT formation. Pericyte depletion through inducible endothelial-specific knockout of Pdgf-b decreases NVT formation and impairs revascularization. Inactivation of the NCK1 and NCK2 adaptor proteins inhibits pericyte migration by preventing PDGF-B-induced phosphorylation of PDGFRβ at Y1009 and PAK activation. Loss of Nck1 and Nck2 in mural cells prevents NVT formation and vascular leakage and promotes revascularization, suggesting PDGFRβ-Y1009/NCK signaling as a potential target for the treatment of retinopathies.

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Citations

Nov 5, 2019·Current Stem Cell Research & Therapy·L Vinod Kumar ReddyDwaipayan Sen
May 30, 2020·Journal of the American Heart Association·Mabruka AlfaidiA Wayne Orr
May 20, 2020·The Journal of Clinical Investigation·Mabruka AlfaidiA Wayne Orr
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Jun 15, 2021·Frontiers in Cell and Developmental Biology·Mabruka AlfaidiAnthony Wayne Orr
Feb 15, 2020·Molecular Therapy. Methods & Clinical Development·Annabelle SchlüterDaniela Mauceri
Oct 17, 2021·Journal of Cardiovascular Pharmacology·Tianyou WangZhongqun Wang

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Methods Mentioned

BETA
GTPases
transfection
PCR

Clinical Trials Mentioned

NCT01944839

Software Mentioned

Leica application suite advanced fluorescence ( LAS - AF )
Prism
GraphPad
ImageJ

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