Vascular Endothelial Growth Factor Receptor-2 Induces Survival of Hematopoietic Progenitor Cells

Bruno Larrivée,David R Lane,Ingrid Pollet,Peggy L Olive,R Keith Humphries,Aly Karsan

doi:10.1074/jbc.m212158200

Abstract

Vascular endothelial growth factor (VEGF) and its receptors play an essential role in the formation and maintenance of the hematopoietic and vascular compartments. The VEGF receptor-2 (VEGFR-2) is expressed on a population of hematopoietic cells, although its role in hematopoiesis is still unclear. In this report, we have utilized a strategy to selectively activate VEGFR-2 and study its effects in primary bone marrow cells. We found that VEGFR-2 can maintain the hematopoietic progenitor population in mouse bone marrow cultured in the absence of exogenous cytokines. Maintenance of the hematopoietic progenitor population is due to increased cell survival with minimal effect on proliferation. Progenitor survival is mainly mediated by activation of the phosphatidylinositol 3'-kinase/Akt pathway. Although VEGFR-2 also activated Erk1/2 mitogen-activated protein kinase, it did not induce cell proliferation, and blockade of this pathway only partially decreased VEGFR-2-mediated survival of hematopoietic progenitors. Thus, the role of VEGFR-2 in hematopoiesis is likely to maintain survival of hematopoietic progenitors through the activation of antiapoptotic pathways.

Highlights

Vascular endothelial growth factor (VEGF) and its receptors play an essential role in the formation and maintenance of the hematopoietic and vascular compartments
Activation of VEGF receptor-2 (VEGFR-2) Delays Loss of Murine Hematopoietic Progenitors—To study the effect of VEGFR-2 signaling in primary bone marrow cells independently of other VEGF receptors, including VEGFR-1, VEGFR-3, neuropilin-1, or neuropilin-2 [15], or the presence of endogenous VEGF, we used a VEGFR-2 Signaling in Hematopoietic Progenitors strategy to dimerize the intracellular domain of VEGFR-2 with a chemical inducer, AP20187
We cloned the intracellular domain of VEGFR-2 and fused it to a modified FK506-binding protein (FKBP) domain that can be dimerized with a chemical inducer, AP20187 (Fig. 1A)

Summary

Introduction

Vascular endothelial growth factor (VEGF) and its receptors play an essential role in the formation and maintenance of the hematopoietic and vascular compartments. Activation of VEGFR-2 Delays Loss of Murine Hematopoietic Progenitors—To study the effect of VEGFR-2 signaling in primary bone marrow cells independently of other VEGF receptors, including VEGFR-1, VEGFR-3, neuropilin-1, or neuropilin-2 [15], or the presence of endogenous VEGF, we used a VEGFR-2 Signaling in Hematopoietic Progenitors strategy to dimerize the intracellular domain of VEGFR-2 with a chemical inducer, AP20187.

Results

Conclusion