Format

Send to

Choose Destination
See comment in PubMed Commons below
Circ Res. 2013 Jun 21;113(1):32-9. doi: 10.1161/CIRCRESAHA.113.301407. Epub 2013 May 9.

Endothelial Shc regulates arteriogenesis through dual control of arterial specification and inflammation via the notch and nuclear factor-κ-light-chain-enhancer of activated B-cell pathways.

Author information

1
Department of Genetics, Curriculum in Genetics and Molecular Biology, Department of Cell and Molecular Physiology, Department of Medicine, Division of Hematology and Oncology, and McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Abstract

RATIONALE:

Arteriogenesis, the shear stress-driven remodeling of collateral arteries, is critical in restoring blood flow to ischemic tissue after a vascular occlusion. Our previous work has shown that the adaptor protein Shc mediates endothelial responses to shear stress in vitro.

OBJECTIVE:

To examine the role of the adaptor protein Shc in arteriogenesis and endothelial-dependent responses to shear stress in vivo.

METHODS AND RESULTS:

Conditional knockout mice in which Shc is deleted from endothelial cells were subjected to femoral artery ligation. Hindlimb perfusion recovery was attenuated in Shc conditional knockout mice compared with littermate controls. Reduced perfusion was associated with blunted collateral remodeling and reduced capillary density. Bone marrow transplantation experiments revealed that endothelial Shc is required for perfusion recovery because loss of Shc in bone marrow-derived hematopoietic cells had no effect on recovery. Mechanistically, Shc deficiency resulted in impaired activation of the nuclear factor κ-light-chain-enhancer of activated B-cell-dependent inflammatory pathway and reduced CD45⁺ cell infiltration. Unexpectedly, Shc was required for arterial specification of the remodeling arteriole by mediating upregulation of the arterial endothelial cell marker ephrinB2 and activation of the Notch pathway. In vitro experiments confirmed that Shc was required for shear stress-induced activation of the Notch pathway and downstream arterial specification through a mechanism that involves upregulation of Notch ligands delta-like 1 and delta-like 4.

CONCLUSIONS:

Shc mediates activation of 2 key signaling pathways that are critical for inflammation and arterial specification; collectively, these pathways contribute to arteriogenesis and the recovery of blood perfusion.

KEYWORDS:

NF-κB; Notch; Shc; arteriogenesis; shear stress

PMID:
23661718
PMCID:
PMC3918667
DOI:
10.1161/CIRCRESAHA.113.301407
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center