PTP1b is a Physiologic Regulator of VEGF Signaling in Endothelial Cells
Background—Regulation of vascular endothelial growth factor receptor-2 (VEGFR2) signaling is a control point that determines the extent of vascular tree formation. Recent studies demonstrated an important role played by VEGFR2 endothelial trafficking in control of its activity and suggested the involvement of a phosphotyrosine phosphatase 1b (PTP1b) in this process. This study was designed to define the role of PTP1b in endothelial VEGFR2 signaling and its role in regulation of angiogenesis and arteriogenesis.
Methods and Results—We generated mice carrying an endothelial-specific deletion of PTP1b and examined the effect of this knockout on VEGF signaling, angiogenesis and arteriogenesis in vitro and in vivo. PTP1b knockout endothelial cells had increased VEGF-dependent activation of ERK signaling, sprouting, migration and proliferation compared to controls. Endothelial PTP1b null mice had increased retinal and Matrigel implant angiogenesis, accelerated wound healing pointing to enhanced angiogenesis. Increased arteriogenesis was demonstrated by observations of faster recovery of arterial blood flow and large numbers of newly formed arterioles in the hindlimb ischemia mouse model. PTP1b endothelial knockout also rescued impaired blood flow recovery after common femoral artery ligation in synectin null mice.
Conclusions—PTP1b is a key regulator of endothelial VEGFR2 signaling and plays an important role in regulation of the extent of vascular tree formation.
- endothelial cell
- vascular endothelial growth factor receptor
- vascular endothelial growth factor
- Received February 26, 2014.
- Revision received June 23, 2014.
- Accepted June 26, 2014.