VEGFR has strong tyrosine kinase activity, and transduces the major signals for angiogenesis.VEGFR is a direct signal transducer for pathological angiogenesis including cancer and diabetic retinopathy, thus, VEGFR itself and the Stugeron signaling appear to be critical targets for the suppression of these diseases.VEGFR plays dual role, a negative role in angiogenesis in the embryo most likely by trapping VEGFA, and a positive role in adulthood in a tyrosine kinasedependent manner.VEGFR is expressed not only in endothelial cells but also in macrophagelineage cells, and promotes tumor growth, metastasis, and inflammation.Furthermore, a soluble form of VEGFR was found to be present at abnormally high levels in the serum of preeclampsia patients, and induces proteinurea and renal dysfunction.Therefore, VEGFR is also an important target in the treatment of human diseases.Interestingly, the activation of VEGFR via VEGFE in vivo results in a strong angiogenic response in mice with minor side effects such as inflammation compared with VEGFA, suggesting VEGFE to be a novel material for proangiogenic therapy.Furthermore, the progression of major diseases such as cancer and diabetic retinopathies is closely related to abnormal increases in the vascular networks. Other important diseases such as cardiac infarction and brain infarction, however, are caused by poor blood supply, resulting in the severe damage of these tissues and leading to ischemic cell death.To overcome diseases related to vascular systems, an understanding of the molecular basis of angiogenesis is necessary.Extensive studies have been carried out during the past two decades, and several factors including vascular endothelial growth factor, and ephrins were found to be major contributors.Among them, VEGF and its receptor system is involved in the formation of blood vessels and lymph vessels in mammals from the earliest stages of embryogenesis. VEGFA is the major player in angiogenesis among the VEGF family, and activates two tyrosine kinase receptors, VEGFR. VEGFR has a very tight ligandbinding Piperonyl butoxide domain for VEGFA, whereas VEGFR has strong tyrosine kinase activity, and the two play different roles in angiogenesis through unique molecular mechanisms.DVEGFR is used mainly for cell migration such as the migration of border cells, hematopoietic cells, and epithelial cells for thorax closure. Therefore, the signaling mechanisms of these receptors are suggested to have phylogenetically developed in a stepwise manner. Structure of VEGFR and VEGFR VEGFR and VEGFR consist of and amino acids in humans, respectively, and can be separated into regions; the extracellular ligandbinding domain, transmembrane domain, tyrosine kinase domain, and downstream carboxy terminal region. The tyrosine kinase domain of VEGFR and R is separated into two portions with an approximately amino acidlong kinaseinsert sequence. The length of the kinase insert is similar to that of members of the PDGFR family, however, the structure is quite different. These cells form blood islands at yolk sac, and start hematopoiesis. From the postnatal to adult stages, VEGFR is expressed mostly on vascular endothelial cells.VEGFR is also expressed in a fraction of hematopoietic cells which might be the progenitor for endothelial cells. However, the expression level appears significantly lower than that in endothelial cells, thus, it is unclear whether VEGFR at low levels in these cells could play a biological role or not.