Endothelial Shc Regulates Arteriogenesis Through Dual Control of Arterial Specification and Inflammation via the Notch and NF-κB Pathways
Rationale: Arteriogenesis, the shear stress-driven remodeling of collateral arteries, is critical in restoring blood flow to ischemic tissue following 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 to 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 as loss of Shc in bone marrow-derived hematopoietic cells had no effect on recovery. Mechanistically, Shc deficiency resulted in impaired activation of the NF-κB-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 two key signaling pathways that are critical for inflammation and arterial specification; collectively, these pathways contribute to arteriogenesis and recovery of blood perfusion.
- Received March 20, 2013.
- Revision received May 8, 2013.
- Accepted May 9, 2013.