ABSTRACT
Background................................................................................................... 38 Structure and gene expression of VEGF receptors ................................ 38
Seven-Ig type TK with long kinase insert .................................. 38 High-affinity binding regions of VEGFRs for VEGF-A............ 40
Biological activities of VEGF receptors .................................................... 41 Angiogenesis and endothelial cell growth: different roles of
VEGFR1 and VEGFR2 in vasculogenesis and angiogenesis during early development in mice ........................................... 41
VEGFR1 TK (–/–) and VEGFR1 TM-TK (–/–) mice indicate unique features of TK and TM domains in VEGFR1 ............ 41
Vascular permeability..................................................................... 42 Cytokine production and communications with other cells ... 42
Signal transduction from VEGF receptors............................................... 43 Cell growth signal........................................................................... 43 Cell survival signal ......................................................................... 45 Cell migration signal ...................................................................... 45 Vascular permeability..................................................................... 46
Involvement of VEGFRs in various diseases .......................................... 46 Carcinogenesis and tumor metastasis ......................................... 46 Rheumatoid arthritis, atherosclerosis, and psoriasis ................ 46 Abnormal up-regulation of soluble VEGFR1 in pre-eclampsia ................................................................................... 47
Inhibitors and artificial modulators of VEGFRs for clinical use .............................................................................................. 47 References...................................................................................................... 48
Background Blood vessel formation and remodeling are essential for the development of tissues in the vertebrate body.1 Among angiogenic factors identified to date, the VEGF family (particularly, VEGF-A) is considered to be the fundamental regulator in angiogenesis at embryogenesis.2 VEGF-A gene-deficient mice, even in the heterozygote condition, die in the embryonic stage due to multiple defects of angiogenesis, strongly suggesting that appropriate levels of VEGF-A and its signaling via receptors are essential for the establishment of the closed circulatory system in vertebrates.3-6
In addition to the VEGF-VEGFR system, various signaling systems such as angiopoietin-Tie2, ephrinB2-EphB4, PDGF-PDGFR, matrix metalloproteinases, etc. are involved in the development of the circulatory system. These systems are the regulators for the interaction and stabilization of smooth muscle cells with endothelial cells, arterio-venous differentiation, and sprouting/cell migration. Elucidating the cross-talk between the VEGF-VEGFR system and these angiogenic modulator systems is important for understanding the whole process of angiogenesis signaling and its remodeling.
