VEGF-VEGFR System as a Target for Suppressing Inflammation and other Diseases

The vascular endothelial growth factor (VEGF)-VEGF receptor (R) system is deeply involved in angiogenesis and lymphangiogenesis. VEGFR1/ Fms-like tyrosine kinase-1 (Flt-1) and VEGFR2 are significantly expressed in vascular endothelial cells, where they transfer proangiogenic signals. Particularly, VEGFR2 has strong tyrosine kinase activity; thus, the major and direct angiogenic signals are generated from VEGFR2. VEGFR3 is specifically expressed in lymphatic endothelial cells, generating the main signal for lymphangiogenesis. In addition, VEGFR1 is wellexpressed on the membrane of macrophage lineage cells such as monocytes, transducing an important signal for the migration and cytokine/chemokine production of these cells. This VEGFR1-macrophage axis stimulates seemingly non-inflammatory and inflammatory responses in various tissues and promotes a variety of diseases such as tumor growth via proangiogenesis, tumor metastasis, lymphangiogenesis, arthritis, and atherosclerosis. This axis is also important for the physiological recovery systems like bone marrow reconstitution and wound healing. VEGFR1 expresses two forms of mRNA: one for the full-length VEGFR1/Flt-1 receptor with tyrosine kinase; the other for a soluble form carrying only the ligand-binding region (sFlt-1/soluble VEGFR1) that functions as a decoy receptor by trapping its ligands VEGF-A, PlGF, and VEGF-B. Therefore, the VEGFR1-dependent inflammatory and non-inflammatory reactions are also regulated by a balance of gene expression between full-length and soluble forms of VEGFR1/Flt-1. Taken together, these findings suggest that VEGF-VEGFR signal is an important target for suppressing various diseases including inflammation.