Disease relevance of Kdr

• Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality [1].
• When similar combination was applied to the H460 lung cancer xenograft model in nude mice, loss of radiation-induced phosphorylated Flk-1 was observed in the combination treatment group, which also showed a large decrease in tumor vascular density by staining of the von Willebrand factor [2].
• Overexpression of VEGF 121 in immortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the VEGF receptors VEGFR-1 and VEGFR-2 in vivo [3].
• Circulating leukocytes and thrombocytes were increased in irradiated SCID (H2K(d)) mice transplanted with ES cell-derived Flk1+ cells compared with vehicle-injected control mice [4].
• Increased expression of KDR/Flk-1 (VEGFR-2) in murine model of ischemia-induced retinal neovascularization [5].
• We also examined whether ischaemic preconditioning (PC), a novel method to induce cardioprotection against ischaemia reperfusion injury, through stimulating the VEGF signalling pathway might function in Flk-1(+/-) mice [6].

High impact information on Kdr

• Mouse embryos lacking the receptor tyrosine kinase, Flk1, die without mature endothelial and hematopoietic cells [7].
• To investigate the role of Flk1 during vasculogenesis and hematopoiesis, we examined the developmental potential of Flk1-/- embryonic stem cells in chimeras [7].
• A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis [7].
• We also demonstrate that cells lacking Flk1 are unable to reach the correct location to form blood islands, suggesting that Flk1 is involved in the movement of cells from the posterior primitive streak to the yolk sac and, possibly, to the intraembryonic sites of early hematopoiesis [7].
• Studies using hepatocyte-specific deletion of the Vegfa gene and hepatocyte-endothelial cell cocultures indicated that blockade of VEGF induced hepatic Epo by interfering with homeostatic VEGFR2-dependent paracrine signaling involving interactions between hepatocytes and endothelial cells [8].

Chemical compound and disease context of Kdr

• These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC [9].
• The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell-specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis [10].
• Furthermore, we investigated the effectiveness of recombinant soluble Flk-1 adenovirus on inhibition of tumor growth in an ovarian tumor (SKOV3) nude murine model, combined with cis-diamminedichloroplatinum (DDP) [11].
• Flk-1 was previously shown to play a role in angiogenesis and tumor formation of s.c. xenografts of C6 glioma cells using dominant-negative methodology [12].
• Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice [13].

Biological context of Kdr

• However, Flk1(-/Tal1) embryonic stem (ES) cells were capable of blast colony formation in vitro at levels equivalent to Flk1(+/-) heterozygotes [14].
• Thus, VEGFR2 signaling is required for the endothelial differentiation of mouse ES cells induced by VEGF-C, and VEGFR3 signaling may confer lymphatic endothelial-like phenotypes to ECs [15].
• We show that ionizing radiation induces expression of phosphorylated VEGFR-2 (Flk-1) in endothelial cells and that this phosphorylation is inhibited by AZD2171 [2].
• 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 [16].
• In addition, Plcg1 nullizygous embryos express a greatly reduced level of vascular endothelial growth factor receptor-2/Flk-1, consistent with significantly impaired vasculogenesis and erythropoiesis [17].

Anatomical context of Kdr

• We propose a model in which the combinatorial effects of Flk1 and Tal1 act to regulate cell fate choice in early development into hematopoietic, endothelial, and smooth muscle lineages [14].
• We have cloned a receptor tyrosine kinase cDNA, designated fetal liver kinase 1 (Flk-1), from mouse cell populations enriched for hematopoietic stem and progenitor cells [18].
• We also demonstrate by in situ hybridization that Flk-1 protein expression in the mouse embryo is restricted to the vascular endothelium and the umbilical cord stroma [19].
• A chemically defined culture of VEGFR2+ cells derived from embryonic stem cells reveals the role of VEGFR1 in tuning the threshold for VEGF in developing endothelial cells [20].
• Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-receptor 2 and host VEGF-A [16].

Associations of Kdr with chemical compounds

• Expression of platelet endothelial cell adhesion molecule, a measure of small vessel density, and endothelial nitric oxide synthase (NOS), a downstream target of VEGFR2, were increased at 48 and 72 h following toxic doses of APAP, and treatment with SU5416 decreased their expression [21].
• Our data demonstrate that VEGF analogs increase vascular permeability through VEGFR-2 activation, and that both endogenous PAF and NO synthesis contribute to VEGF-A(165)-mediated vascular permeability [22].
• Histological analyses of lung lesions revealed that ZD6474 treatment inhibited activation of VEGFR-2 and reduced tumor vascularization and tumor cell proliferation [9].
• Therapeutic effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib was inactive in this model [9].
• A vascular endothelial growth factor receptor-2 kinase inhibitor potentiates the activity of the conventional chemotherapeutic agents paclitaxel and doxorubicin in tumor xenograft models [23].

Physical interactions of Kdr

• Vascular endothelial growth factor receptor 2 (VEGFR-2) is present in regions of cell-cell contact and coimmunoprecipitates with VE-cadherin [24].
• A tandem HIF-2alpha/Ets binding site was identified within the Flk-1 promoter that acted as a strong enhancer element [25].
• As VEGF-C also binds VEGFR-2, which is expressed in lymphatic endothelia, it is not clear which receptors are responsible for the lymphangiogenic effects of VEGF-C [26].

Regulatory relationships of Kdr

• In this study, we report that stable overexpression of VE-cadherin in two different endothelial cells induced an increase in VEGFR-2 protein levels [24].
• Shb promotes blood vessel formation in embryoid bodies by augmenting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-beta signaling [27].
• The increase in VEGFR-2 was also induced by overexpression of other classical cadherins such as E-cadherin or N-cadherin [24].
• Flk1+ cells expressed c-kit predominantly [4].
• Here we show that Runx1 represses Flk-1 during the development of hemogenic endothelial cells into hematopoietic cells [28].

Other interactions of Kdr

• Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse [14].
• Chromosomal mapping shows that the Flk-1, Kit, and Pdgfra genes are closely linked [18].
• These results suggested that greater requirement of VEGF in the maintenance than induction of ECs was due to the activity of VEGFR1 sequestering VEGF from VEGFR2 signal [20].
• This result provides new insights into the involvement of VEGFR-3 signals in the maintenance of vascular integrity through modulation of VEGFR-2 signals [29].
• Deregulation of Flk-1/vascular endothelial growth factor receptor-2 in fibroblast growth factor receptor-1-deficient vascular stem cell development [30].

Analytical, diagnostic and therapeutic context of Kdr

• This response may be the consequence of an increased number of VEGFR-2 positive cells at an early stage of EB development, a finding corroborated by both immunostaining and real-time RT-PCR [27].
• Microarray analysis of VEGFR-2/CD31 positive cells after 6 days of differentiation revealed numerous changes of expression of genes relating to an endothelial/hematopoietic phenotype in response to Shb overexpression [27].
• Administration of either anti-VEGFR-1 or anti-VEGFR-2 alone failed to inhibit allograft rejection [31].
• CONCLUSION: The Flk1+ hematopoietic cells derived from ES cells reconstitute hematopoiesis in vivo and may become an alternative donor source for bone marrow transplantation [4].
• Northern blot analysis demonstrated that the mRNA levels of KDR/Flk-1 were greater in the neovascular retina of hypoxic animals than in control animals [5].

References