Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells: Possible role in the hematopoietic microenvironment

Objective. In the hematopoietic microenvironment, bone marrow endothelial c ells may play an important role in trafficking and maintenance of progenito r and stem cells due to adhesive interactions and paracrine secretion of he matopoietic growth factors. However, it is unknown whether progenitors in t urn modulate endothelial proliferation and function. Materials and Methods. We analyzed mRNA expression (Northern blot) and rele ase of vascular endothelial growth factor-A (VEGF-A), which specifically ac ts on endothelial cells, by cytokine-stimulated peripheral blood-derived CD 34+ hematopoietic progenitor cells. Results. While unstimulated CD34+ cells expressed VEGF-A mRNA weakly withou t cytokine release in vitro, incubation for 24 hours with a single cytokine (e.g., kit ligand [KL]) resulted in increased VEGF-A mRNA expression and s ignificant secretion of VEGF-A into the supernatant. The amount of VEGF rel eased was substantially augmented by incubation with a combination of cytok ines (e.g., KL, IL-3, GM-CSF, G-CSF), or by exposure to hematopoietic cytok ines for a longer time period. In addition, we show that VEGF induced the r elease of hematopoietic growth factors (GM-CSF) by bone marrow endothelial cells and that in vitro stromal cell-derived factor-1 (SDF-1) driven transe ndothelial progenitor cell migration was increased by the presence of VEGF, which might be due to pore formation (increased endothelial fenestration). Conclusions. In vivo, release of VEGF by progenitor cells may result in a p aracrine loop supporting proliferation of both endothelium and progenitors and may facilitate transendothelial migration during cytokine-induced proge nitor cell mobilization. (C) 2000 International Society for Experimental He matology. Published by Elsevier Science Inc.