title: Folic acid inhibits endothelial cell migration through inhibiting the RhoA activity mediated by activating the folic acid receptor/cSrc/p190RhoGAP-signaling pathway.
abstract: Previously, our in vivo studies demonstrated that folic acid (FA) could inhibit angiogenesis and in vitro studies showed that FA reduced vascular endothelial cell proliferation through activating the cSrc/ERK-2/NFκB/p53 pathway mediated by FA receptor (FR). Here, we further examined the effect of FA on endothelial cell migration. Our results showed that FA (10 μM) inhibited the formation of lamellipodia, migration and capillary-like tube formation of human umbilical venous endothelial cells (HUVEC). These inhibition effects induced by FA treatment were not due to reduction of cell survival and cell adhesion on the collagen-coated plate. Treatment of HUVEC with FA (10 μM) increased the activity of cSrc and p190RhoGAP and decreased the activity of RhoA. Over-expression of the constitutively active RhoA construct (RhoA V14) prevented the FA-induced inhibition of migration and capillary-like tube formation in HUVEC. However, these preventive effects were abolished by pretreatment of HUVEC with a ROCK inhibitor, Y27632. Pretreatment with a cSrc inhibitor, PP2, prevented the FA-induced activation of p190GAP, reduction of the RhoA activity and migration inhibition in HUVEC. Moreover, pre-transfection with p190RhoGAP siRNA abolished the FA-induced reduction in the RhoA activity and migration inhibition in HUVEC. Taken together, our results suggest that FA might inhibit endothelial cell migration through inhibiting the RhoA activity mediated by activating the FR/cSrc/p190RhoGAP-signaling pathway. These findings further support the anti-angiogenic activity of FA.
authors.affiliation: Department of Medicine, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tien-Chi
authors.initials: TC
authors.lastname: Hou
authors.forename: Jheng-Jhe
authors.initials: JJ
authors.lastname: Lin
authors.forename: Heng-Ching
authors.initials: HC
authors.lastname: Wen
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Chen
authors.forename: Sung-Po
authors.initials: SP
authors.lastname: Hsu
authors.forename: Wen-Sen
authors.initials: WS
authors.lastname: Lee
mesh_terms: D002448:Cell Adhesion; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005492:Folic Acid / Q000494:pharmacology*; D058972:Folic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D016391:Genes, src / Q000235:genetics / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C074560:ARHGAP35 protein, human; D058972:Folic Acid Transporters; D020662:Guanine Nucleotide Exchange Factors; D012097:Repressor Proteins; D005492:Folic Acid; D020742:rhoA GTP-Binding Protein