Disease relevance of Flt4

• Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3 [1].
• Primary human lymphedema (Milroy's disease), characterized by a chronic and disfiguring swelling of the extremities, is associated with heterozygous inactivating missense mutations of the gene encoding vascular endothelial growth factor C/D receptor (VEGFR-3) [2].
• Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter [3].
• In summary, kCYC expression within VEGFR-3(+) cells of mice causes marked impairment of lymphatic function. kCYC may contribute to the development of certain clinical and histologic features of KS, including localized edema and retention of extravasated erythrocytes within KS tumors [3].
• Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer [4].

High impact information on Flt4

• In addition, an abnormally large proportion of skin lymphatic vessels was covered with smooth muscle cells in individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4) [5].
• Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3 [6].
• Vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to stimulate lymphangiogenesis and their receptor, VEGFR-3, has been linked to human hereditary lymphedema [6].
• Unlike VEGF, the related VEGF-C stimulates the growth of lymphatic vessels through its specific lymphatic endothelial receptor VEGFR-3 [7].
• 5. Thus, VEGFR-3 has an essential role in the development of the embryonic cardiovascular system before the emergence of the lymphatic vessels [7].

Chemical compound and disease context of Flt4

• Heterozygous inactivation of the VEGFR-3 tyrosine kinase leads to primary lymphedema due to defective lymphatic drainage in the limbs [8].

Biological context of Flt4

• We further find that Flt4, a receptor for Vegfc, cooperates with Kdr during artery morphogenesis, but not differentiation [9].
• Recombinant Flt4-L activated Flt4 as judged by induction of tyrosyl phosphorylation, and induced mitogenesis in vitro of lymphatic endothelial cells [10].
• Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3), a receptor for VEGF-C, was shown to be essential for angiogenesis as well as for lymphangiogenesis [11].
• These data suggest that VEGFR-2 signaling is critical for tumor angiogenesis and vascular permeability and that VEGFR-3 signaling does not compensate for VEGFR-2 blockade [12].
• These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo [13].

Anatomical context of Flt4

• When induced in beta-galactosidase knock-in Flt4(+/-) mice, the tumor endothelia could be stained blue in a number of tumor cells although the staining was of lower intensity than in normal lymphatic vessels [14].
• The Flk-1 and Flt4 receptors were also identified in immunoblots of the tumors and in cells cultured from them [14].
• To elucidate the roles of VEGFR3 signaling in the differentiation of vascular progenitor cells into ECs, we introduced various types of VEGFR3 cDNAs into mouse ES cells [15].
• Here it is shown that targeted inactivation of the gene encoding VEGFR-3 resulted in defective blood vessel development in early mouse embryos [7].
• The VEGFR-3 ligand VEGF-C stimulates lymphangiogenesis in transgenic mice and in chick chorioallantoic membrane [13].

Associations of Flt4 with chemical compounds

• Hence, VEGFR-3 is another receptor tyrosine kinase involved in tumor-induced angiogenesis [16].
• Vegf-d, a secreted glycoprotein, is one of two known activating ligands for Vegfr-3, the other being Vegf-c. Vegf-d stimulates lymphangiogenesis in tissues and tumors; however, its role in embryonic development was previously unknown [17].

Physical interactions of Flt4

• Both swaps conferred upon Flt-4 the ability to bind VEGF with an affinity nearly identical to that of wild-type Flt-1 [18].

Regulatory relationships of Flt4

• Furthermore, administration of blocking anti-VEGFR-3 antibodies inhibited the FGF-2-induced lymphangiogenesis [19].

Other interactions of Flt4

• This result provides new insights into the involvement of VEGFR-3 signals in the maintenance of vascular integrity through modulation of VEGFR-2 signals [11].
• In contrast, interference with the Flt-4 pathway or the Tie-1 pathway was without significant effect [20].
• A contig of 24 YACs and 13 P1 clones has been assembled and spans approximately 3 Mb from Flt4 to Tcf7 [21].
• Administration of neutralizing antibodies against either VEGF receptor-3 or VEGF receptor-2 impaired vascular network formation, whereas neutralizing antibodies against VEGF receptor-1 potentiated development of immature vascular structures [22].
• VEGF receptor-3 expression was confined to vascular endothelial cells and analysis of the lymphatic marker Prox-1 revealed no expansion of lymphatic endothelial cells [22].

Analytical, diagnostic and therapeutic context of Flt4

• In this study we used an in vitro embryonic stem (ES) cell culture system to maintain the VEGFR-3(+) endothelial cell (EC) and investigated the role of VEGFR-3 signals at the cellular level [11].
• The authors analyzed the function of VEGF-C signaling through both VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis using a coculture of para-aortic splanchnopleural mesoderm (P-Sp) explants from mouse embryos with stromal cells (OP9) [23].
• Expression of lymphatic-specific markers (Flt-4, LYVE-1, Prox-1) and the tight junction proteins (ZO-1) were examined by RT-PCR, immunoblotting, and fluorescent microscopy [24].
• Our results show that antibody interference with VEGFR-3 function can inhibit the growth of several human tumor xenografts in immunocompromised mice [25].
• Immunofluorescence double staining for CD11b, CD11c, CD31, CD45, GR-1, CD3, CD80, LYVE-1 and class II major histocompatibility complex (MHC) antigen expression, using confocal microscopy, was performed to further phenotype the VEGFR-3+ cells [26].

References