Abstract
Vascular endothelial growth factor (VEGF) regulates vasculogenesis and angiogenesis by signaling through two tyrosine kinase receptors, VEGF receptor-1(VEGFR1) and VEGFR2. Whereas VEGF/VEGFR2 signaling contributes to the regulation of endothelial cell lineage differentiation and proliferation, VEGF/VEGFR1 signaling in hematopoietic lineage cells can promote the mobilization of hematopoietic stem cells and induce bone marrow regeneration. These data suggest that there is a significant interaction between post-natal angiogenesis and hematopoiesis.
We reported that the activation of VEGF/VEGFR and chemokine stromal cell-derived factor-1(CXCL12)/CXCR4 signal pathways induce the mobilization of bone marrow-derived hematopoietic lineage cells. It was shown that these pathways regulate bone marrow cell differentiation and proliferation by activating matrix metalloproteinases (MMP) causing MMP-mediated hematopoietic factor, Kit ligand processing. Moreover, we have also reported that CXCL12 and VEGF are released from bone marrow-derived inflammatory cells like neutrophils or platelets.
It was demonstrated that CXCR4 positive and VEGFR1 positive lineage cells, also called hemangiocytes, can produce angiopoetin-2 which can recruit hematopoietic stem cells from the bone marrow and work as molecular HUB by augmenting revascularization in the “neo-vascular niche”. Recently, we showed that activation of the fibrinolytic system resulted in the constitutive activation of MMPs causing Kit ligand release, which promoted bone marrow regeneration after myelosuppression. These data imply that the fibrinolytic system might also play a role in regulating neoangiogenesis during tissue regeneration. Here, we will introduce recent studies from our group and several novel concepts in our current understanding of the regulation of angiogenesis.
