Disease relevance of KDR

• Hypertension increased retinal KDR expression 67 +/- 42% (P < 0.05) in SHR rats compared with normotensive WKY control animals [1].
• The HRE conferred hypoxia inducibility to the KDR and E-selectin promoters [2].

High impact information on KDR

• Placenta growth factor, which binds to Flt-1/VEGF-R1 but not Flk-1/KDR/VEGF-R2 receptor tyrosine kinase, failed to increase permeability [3].
• The PKC inhibitor reduced Ang II-induced KDR mRNA expression by 70+/-15% [4].
• The Ang II-induced KDR mRNA increase was inhibited by either [Sar1,Ile8]angiotensin or angiotensin type 1 receptor antagonists but was not significantly altered by angiotensin type 2 receptor antagonists [4].
• We also found that bisphenol A diglycidyl ether, a PPARgamma antagonist, partially inhibited troglitazone-stimulated NO production with a concomitant reduction in VEGF-KDR/Flk-1-Akt-mediated eNOS-Ser(1179) phosphorylation but with no alteration in eNOS-Ser(116) dephosphorylation induced by troglitazone [5].
• These data are the first to establish a critical role of Flk-1/KDR in S1P-stimulated eNOS phosphorylation and activation [6].

Chemical compound and disease context of KDR

• When hypertension was reduced using captopril or candesartan, retinal KDR expression returned to baseline levels [1].
• These data suggest that hypoxia induces an initial decline in KDR mRNA levels and VEGF binding sites as mediated through adenosine binding to the A2R [7].

Biological context of KDR

• Our study suggests that S1P activation of eNOS involves G(i), calcium, and Src family kinase-dependent transactivation of Flk-1/KDR [6].
• Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitro [8].
• Vascular endothelial growth factor-dependent down-regulation of Flk-1/KDR involves Cbl-mediated ubiquitination. Consequences on nitric oxide production from endothelial cells [9].
• VEGF internalization and subsequent nuclear accumulation only occurred for a short period of time after the wounding and was specifically abolished by antibodies that bind to the KDR binding site of VEGF [10].
• In an attempt to increase expression but to preserve the tissue specificity we have examined hypoxic and cytokine-inducible enhancer elements in combination with the KDR and E-selectin promoters [2].

Anatomical context of KDR

• We now report that S1P treatment of bovine aortic endothelial cells acutely increases the tyrosine phosphorylation of Flk-1/KDR, similar to VEGF treatment [6].
• In the present study, we demonstrate the expression of Flt, but not KDR, in bovine retinal pericytes (BRPCs) [11].
• Double-label analysis showed that Flk-1/KDR and eNOS colocalize with caveolin-1 in plasma membrane caveolae [12].
• Nuclear translocation of eNOS and Flk-1/KDR within caveolae may represent a mechanism for targeting NO production to the nuclear compartment where it could influence transcription factor activation [13].
• First, we demonstrate that expression of KDR into a CHO cell line deficient in heparan sulfate biosynthesis does not allow VEGF165 binding unless heparin is exogenously added during the binding assay [14].

Associations of KDR with chemical compounds

• Taken together, our results demonstrate that prolonged treatment with troglitazone increases endothelial NO production by at least two independent signaling pathways: PPARgamma-dependent, VEGF-KDR/Flk-1-Akt-mediated eNOS-Ser(1179) phosphorylation and PPARgamma-independent, eNOS-Ser(116) dephosphorylation [5].
• Stretched-induced KDR expression was not inhibited by AT1 receptor blockade using candesartan [1].
• This effect is mediated by a signaling cascade initiated by flk-1/KDR activation of c-Src, leading to phospholipase C gamma1 activation, inositol 1,4,5-trisphosphate formation, release of [Ca(2+)](i) and nitric oxide synthase activation [15].
• DPMA, an adenosine A2 receptor (A2R) agonist, decreased KDR mRNA in a dose-dependent manner with an EC50 of 5 to 10 nM [7].
• A1R antagonists, 8-cyclolentyl-1,3-dipropylxanthine and 8-phenyltheophylline, did not inhibit the hypoxic response of KDR mRNA at A1R inhibitory concentrations but did inhibit the response at A2R effective doses (P = 0.001) [7].

Physical interactions of KDR

• In conclusion, our data demonstrate that VEGF binding to the KDR receptor tyrosine kinase results in an increase in KDR receptor gene transcription and protein expression [8].

Regulatory relationships of KDR

• VEGF-induced KDR expression primarily occurred at the transcriptional level as demonstrated by a luciferase reporter assay system [8].

Other interactions of KDR

• Densitometry showed that Flk-1/KDR, eNOS, and caveolin-1 levels were highest in caveolar fractions [12].
• Inhibition of tyrosine kinase, Src tyrosine kinase, protein kinase C, and mitogen-activated protein kinase activities all blocked VEGF-induced KDR up-regulation [8].

Analytical, diagnostic and therapeutic context of KDR

• Although KDR is expressed predominantly in retinal endothelial cells, Northern blot analysis demonstrated substantial expression of the Flt gene in BRPCs without detection of KDR despite using polyadenylated RNA [11].
• Quantitative polymerase chain reaction analysis demonstrated a 3-fold increase in KDR mRNA levels following VEGF exposure [8].
• Western blot analysis showed a 3-5-fold increase in total KDR protein following 4-day VEGF treatment [8].
• Third, affinity purification of heparin molecules on a KDR-derived peptide affinity column, together with capillary electrophoresis and polyacrylamide electrophoresis analysis, was used to show that the KDR-derived peptide interacts with a specific subset of polysaccharide chains contained in the unfractionated heparin [14].

References