PTP1b Is a Physiologic Regulator of Vascular Endothelial Growth Factor Signaling in Endothelial Cells

Abstract

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 extracellular signal-regulated kinase signaling, sprouting, migration, and proliferation compared with controls. Endothelial PTP1b null mice had increased retinal and Matrigel implant angiogenesis and 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.

Selective Vascular Endothelial Protection Reduces Cardiac Dysfunction in Chronic Heart Failure

“…25 Similarly, mice with endothelial PTP1B deficiency also showed increased vascular endothelial growth factor signaling, together with increased angiogenesis and arteriogenesis in a model of hindlimb ischemia, although cardiac ischemia was not studied in this study. 26 In contrast, in this study, we found no change in cardiac capillary density or MRI-based LV perfusion at 4 months post-MI. Thus, although we cannot exclude that early changes in angiogenesis or perfusion may have occurred in our study, this would suggest that the reduced CHF severity that we observed is to a large extent independent of changes in cardiac angiogenic responses.…”

Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells

“…These data demonstrate that knockdown of PTP1B enhances the formation of new vessels in mouse aortic explants in a 3-dimensional gel-based environment. Along the same line with our findings, mice deficient in PTP1B in endothelial cells exhibited enhanced capillary growth in response to VEGF in matrigel implants (10). Moreover, PTP1B knock-out mice showed increased cardiac angiogenesis post myocardial infarction (27).…”

“…A main finding of this study is that PTP1B is a negative regulator of VEGF-induced angiogenesis in endothelial cells, consistent with the recently unraveled contribution of PTP1B in endothelial cell signaling (8,10,26). In a mouse hindlimb ischemic angiogenesis model, PTP1B expression and activity were increased (8).…”

“…On the other hand, there is evidence showing that PTP1B serves as a negative regulator of VEGF-activated ERK signaling in endothelial cells (8,10). These observations implicate that calpain/PTP1B may be involved in the regulation of VEGF-induced angiogenesis.…”

“…However, the phosphorylation site of VEGFR2 for Akt activation is not well established. Some groups support that VEGF-induced Akt activation is not dependent on the Tyr-1175 site (10,23). Point mutation of VEGFR2 at Y801F, not Y1175F, completely abolished VEGF-induced Akt-S473 phosphorylation and downstream NO production in BAECs, indicating that phosphorylation of VEGFR2 at Tyr-801 may lie specifically upstream of Akt/eNOS activation (23).…”