30]][“Inhibitor R”

. VEGFR is a negative regulator for angiogenesis during embryogenesis.VEGFR gene null mutant mice die early in embryogenesis due to the overgrowth of endothelial cells.The ligandbinding domain of VEGFR without the tyrosine kinase domain rescues this abnormality, suggesting that an important role of VEGFR is efficient trapping of VEGFA in early embryogenesis.Tyr is highly autophosphorylated on VEGFR, but its downstream pathway is not clear yet.. due the overgrowth and disorganization of blood vessels, not due to a poor vascularization.This result strongly suggests that VEGFR plays a negative role by suppressing proangiogenic signals in the early embryo to establish a balance essential for physiological angiogenesis.Since VEGFR has high affinity for VEGFA with weak tyrosine kinase activity, we tested whether the negative role of VEGFR involves the ligandbinding domain or not.Interestingly, knockout mice lacking the TK domain of VEGFR were basically healthy with almost normal blood vessels. These mice showed a defect in the migration of macrophages towards VEGFA.These results clearly indicate that the ligandbinding domain along with the transmembrane domain of VEGFR is sufficient for a suppressive effect on angiogenesis in early embryogenesis. The rate of growth of some tumors is slower in VEGFR TK mice than in the wildtype mice.The molecular mechanisms underlying this phenomemon are under investigation.Since the degree of pulmonary metastasis after the intravenous injection of tumor cells in healthy mice was almost the same between the wildtype and VEGFR TK mice, we hypothesized that in the tumorbearing animals, the lung tissue readily accepts metastasizing tumor cells.These results imply that VEGFR signaling is an important target in the suppression of cancer metastasis.VEGFR could be involved in arthritis via at least two mechanisms; the activation of macrophage functions and an increase in angiogenesis.VEGFR mRNA and its protein are expressed in macrophages, and the expression is upregulated in an activated state. VEGFR is involved in the migration of macrophages towards VEGFA.These results suggest that the direct pathway for the involvement of VEGFR in inflammatory diseases is via the activationlmigration of macrophagelineage cells.Atherosclerosis, bone marrow reconstitution, and others.Recently, several groups described a possible involvement of abnormal angiogenesis in the progression of atherosclerosis.Among various angiogenic factors, VEGF is considered to be important in this disease since treatment with sVEGFR in mouse models of atherosclerosis significantly suppressed the degree of disease. In addition to abnormal angiogenesis, macrophagelineage cells are known to play a critical role in the disease.Further studies are necessary to dissect more clearly which receptor, VEGFR or VEGFR or both, is the target for controlling the progression of atherosclerosis.VEGFR is expressed in cells of the macrophagelineage including osteoclasts which regulate bone marrow remodeling.In opop,VEGFR TK mice, hematopoietic bone marrow can not be reconstituted, resulting in severe marrow fibrosis.Although VEGFR by itself does not generate a strong signal for vascular permeability activitiy, it cooperates with VEGFR to significantly enhance the permeability and is involved in several diseases. Soluble VEGFR is mostly expressed in the trophoblast layer, suggesting an endogenous antagonistic protein makes a barrier between fetal and maternal tissues.We have demonstrated that the gene product, VEGFENZ, activates only VEGFR, and strongly stimulates endothelial cell proliferation.

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