NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy.
Alexandre DubracSteffen E KünzelSandrine H KünzelJinyu LiRachana Radhamani ChandranKathleen MartinDaniel M GreifRalf H AdamsAnne EichmannPublished in: Nature communications (2018)
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.
Keyphrases
- growth factor
- endothelial cells
- blood brain barrier
- high glucose
- induced apoptosis
- vascular endothelial growth factor
- mouse model
- smooth muscle
- vascular smooth muscle cells
- cell cycle arrest
- diabetic rats
- percutaneous coronary intervention
- endoplasmic reticulum stress
- cell proliferation
- cerebral ischemia
- genome wide
- ischemia reperfusion injury
- risk assessment
- transcription factor
- signaling pathway
- diabetic retinopathy
- binding protein
- acute coronary syndrome
- replacement therapy