Format

Send to

Choose Destination
Nat Commun. 2018 Aug 27;9(1):3463. doi: 10.1038/s41467-018-05926-7.

NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy.

Author information

1
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06511, USA. alexandre.dubrac@yale.edu.
2
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06511, USA.
3
Department of Tissue Morphogenesis and University of Münster, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine, 48149, Münster, Germany.
4
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06511, USA. anne.eichmann@yale.edu.
5
INSERM U970, Paris Cardiovascular Research Center, 75015, Paris, France. anne.eichmann@yale.edu.
6
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06520, USA. anne.eichmann@yale.edu.

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.

PMID:
30150707
PMCID:
PMC6110853
DOI:
10.1038/s41467-018-05926-7
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center