title: Vascular endothelial growth factor receptor 1 contributes to Escherichia coli K1 invasion of human brain microvascular endothelial cells through the phosphatidylinositol 3-kinase/Akt signaling pathway.
abstract: Escherichia coli is the most common Gram-negative organism causing neonatal meningitis. Previous studies demonstrated that E. coli K1 invasion of brain microvascular endothelial cells (BMEC) is required for penetration into the central nervous system, but the microbe-host interactions that are involved in this process remain incompletely understood. Here we report the involvement of vascular endothelial growth factor receptor 1 (VEGFR1) expressed on human brain microvascular endothelial cells (HBMEC) in E. coli K1 invasion of HBMEC. Our results showed that treatment of confluent HBMEC with pan-VEGFR inhibitors significantly inhibited E. coli K1 invasion of HBMEC. Immunofluorescence results indicated the colocalization of VEGFR1 with E. coli K1 during bacterial invasion of HBMEC. The E. coli-induced actin cytoskeleton rearrangements in HBMEC were blocked by VEGFR inhibitors but not by VEGFR2-specific inhibitors. The small interfering RNA (siRNA) knockdown of VEGFR1 in HBMEC significantly attenuated E. coli invasion and the concomitant actin filament rearrangement. Furthermore, we found an increased association of VEGFR1 with the p85 subunit of phosphatidylinositol 3-kinase (PI3K) in HBMEC infected with E. coli K1 and that E. coli K1-triggered Akt activation in HBMEC was blocked by VEGFR1 siRNA and VEGFR inhibitors. Taken together, our results demonstrate that VEGFR1 contributes to E. coli K1 invasion of HBMEC via recruitment of the PI3K/Akt signaling pathway.
authors.affiliation: Department of Developmental Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Wen-Gang
authors.initials: WG
authors.lastname: Fang
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Kim
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Chen
mesh_terms: D001921:Brain / Q000098:blood supply* / Q000382:microbiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000382:microbiology*; D004926:Escherichia coli / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D007231:Infant, Newborn; D008833:Microcirculation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1
references.citation: Infect Immun. 1999 May;67(5):2103-9
references.pmid: 10225861
references.citation: Cancer Res. 1996 Aug 1;56(15):3540-5
references.pmid: 8758924
references.citation: Nat Rev Mol Cell Biol. 2006 May;7(5):359-71
references.pmid: 16633338
references.citation: Cell Microbiol. 2002 Aug;4(8):503-14
references.pmid: 12174085
references.citation: Infect Immun. 1985 May;48(2):486-91
references.pmid: 2580792
references.citation: J Biol Chem. 1996 Jul 26;271(30):17629-34
references.pmid: 8663424
references.citation: Mol Cell Biol. 1998 Mar;18(3):1379-87
references.pmid: 9488453
references.citation: FEBS Lett. 2010 Jan 4;584(1):27-32
references.pmid: 19903481
references.citation: Cell. 1993 Mar 12;72(5):767-78
references.pmid: 7680959
references.citation: Semin Neonatol. 2001 Apr;6(2):157-72
references.pmid: 11483021
references.citation: J Biol Chem. 1994 Oct 28;269(43):26988-95
references.pmid: 7929439
references.citation: J Mol Endocrinol. 2006 Oct;37(2):199-212
references.pmid: 17032739
references.citation: J Cell Physiol. 2007 Jul;212(1):236-43
references.pmid: 17311300
references.citation: Mol Biol Cell. 2009 Jan;20(1):544-55
references.pmid: 18987340
references.citation: J Pediatr. 1974 Jul;85(1):128-30
references.pmid: 4604810
references.citation: Nat Med. 1996 Dec;2(12):1371-5
references.pmid: 8946838
references.citation: J Virol. 1998 Jul;72(7):6131-7
references.pmid: 9621077
references.citation: Oncogene. 1995 Jan 5;10(1):135-47
references.pmid: 7824266
references.citation: J Biol Chem. 2000 Nov 24;275(47):36769-74
references.pmid: 10973983
references.citation: J Cell Sci. 2008 Mar 1;121(Pt 5):551-9
references.pmid: 18287584
references.citation: J Biol Chem. 2002 Mar 8;277(10):7875-81
references.pmid: 11751905
references.citation: J Neuroimmunol. 1997 Jun;76(1-2):81-90
references.pmid: 9184636
references.citation: Nat Rev Cancer. 2008 Dec;8(12):942-56
references.pmid: 19029957
references.citation: Neurobiol Aging. 2010 Feb;31(2):175-88
references.pmid: 18462836
references.citation: Bioorg Med Chem Lett. 2002 Oct 7;12(19):2767-70
references.pmid: 12217372
references.citation: J Biol Chem. 1998 Nov 13;273(46):30199-203
references.pmid: 9804776
references.citation: J Biol Chem. 2005 Jan 14;280(2):1321-6
references.pmid: 15520002
references.citation: J Biol Chem. 2005 Mar 18;280(11):9904-12
references.pmid: 15637071
references.citation: Int J Med Microbiol. 2005 Oct;295(6-7):463-70
references.pmid: 16238020
references.citation: Cancer Res. 1999 Jan 1;59(1):99-106
references.pmid: 9892193
references.citation: J Biol Chem. 1995 Sep 1;270(35):20254-7
references.pmid: 7657594
references.citation: Biochemistry. 2008 Mar 18;47(11):3345-51
references.pmid: 18284215
references.citation: Biochem Biophys Res Commun. 2007 May 4;356(2):323-8
references.pmid: 17367763
references.citation: N Engl J Med. 1974 May 30;290(22):1216-20
references.pmid: 4133095
references.citation: Microbes Infect. 2000 Aug;2(10):1237-44
references.pmid: 11008113
references.citation: J Biol Chem. 2000 Dec 29;275(52):40725-31
references.pmid: 11018037
references.citation: Nat Rev Microbiol. 2008 Aug;6(8):625-34
references.pmid: 18604221
references.citation: J Biol Chem. 2009 Jul 17;284(29):19427-36
references.pmid: 19473971
references.citation: Mol Cancer Ther. 2004 Dec;3(12):1639-49
references.pmid: 15634658
references.citation: Infect Immun. 1999 Nov;67(11):5775-83
references.pmid: 10531228
references.citation: Biochem J. 2000 Apr 15;347(Pt 2):501-9
references.pmid: 10749680
references.citation: Br J Pharmacol. 2005 Oct;146(4):568-75
references.pmid: 16086034
references.citation: Nat Rev Genet. 2006 Aug;7(8):606-19
references.pmid: 16847462
references.citation: Exp Cell Res. 2006 Mar 10;312(5):549-60
references.pmid: 16336962