Human apo-lactoferrin enhances angiogenesis mediated by vascular endothelial growth factor A in vivo

被引:42
作者
Norrby, K [1 ]
机构
[1] Univ Gothenburg, Sahlgrenska Acad, Inst Lab Med, Dept Pathol, Gothenburg, Sweden
关键词
angiogenesis; apo-lactoferrin; basic fibroblast growth factor; holo-lactoferrin; lactoferrin; therapeutic angiogenesis; vascular endothelial growth factor;
D O I
10.1159/000078927
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Background: Lactoferrin, LF, a multifunctional iron- and heparin-binding protein, present in exocrine body secretions and leukocytes, is remarkably resistant to proteolysis. Ingested bovine iron- unsaturated LF, apo-bLF, suppresses VEGF-A-mediated angiogenesis in a previously described rat mesentery angiogenesis assay, possibly explaining, at least in part, its established anticancer effect in rats and mice. Methods: Using the same experimental system, we have now studied the effect of (i) ingested human apo-LF, apo-hLF, on angiogenesis mediated by VEGF-A and bFGF, (ii) ingested human iron-saturated LF, holo-hLF, on VEGF-A-mediated angiogenesis and (iii) subcutaneous continuously infused apo-hLF on VEGF-A-mediated angiogenesis. Results: Ingested holo-hLF did not affect VEGF-A-mediated angiogenesis. Ingested apo-hLF (from one and the same batch) significantly enhanced VEGF-A-mediated angiogenesis but did not affect bFGF-mediated angiogenesis. Moreover, subcutaneously infused apo-hLF also significantly stimulated VEGF-A-mediated angiogenesis. Conclusion: Taken together, the data suggest that apo-hLF exerts a specific proangiogenic effect in VEGF-A-mediated angiogenesis. Clearly, human and bovine apo-LF exert opposite effects on VEGF-A-induced angiogenesis. Differences in molecular features between human and bovine LFs of possible significance for the outcome are discussed. In hypoxia, compensatory collateral circulation is mediated primarily by VEGF-A. We hypothesize that systemically administered apo-hLF may promote collateral blood vessel formation at hypoxic sites in normal tissue, thus counteracting ischemia and infarction. Copyright (C) 2004 S. Karger AG, Basel.
引用
收藏
页码:293 / 304
页数:12
相关论文
共 106 条
[1]   Transferrins: Iron release from lactoferrin [J].
Abdallah, FB ;
Chahine, JME .
JOURNAL OF MOLECULAR BIOLOGY, 2000, 303 (02) :255-266
[2]   STRUCTURE OF HUMAN LACTOFERRIN - CRYSTALLOGRAPHIC STRUCTURE-ANALYSIS AND REFINEMENT AT 2.8-A RESOLUTION [J].
ANDERSON, BF ;
BAKER, HM ;
NORRIS, GE ;
RICE, DW ;
BAKER, EN .
JOURNAL OF MOLECULAR BIOLOGY, 1989, 209 (04) :711-734
[3]   HUMAN INTERFERON-INDUCIBLE PROTEIN-10 IS A POTENT INHIBITOR OF ANGIOGENESIS IN-VIVO [J].
ANGIOLILLO, AL ;
SGADARI, C ;
TAUB, DD ;
LIAO, F ;
FARBER, JM ;
MAHESHWARI, S ;
KLEINMAN, HK ;
REAMAN, GH ;
TOSATO, G .
JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 182 (01) :155-162
[4]  
Baker EN, 1998, ADV EXP MED BIOL, V443, P1
[5]   Lactoferrin and transferrin: Functional variations on a common structural framework [J].
Baker, EN ;
Baker, HM ;
Kidd, RD .
BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE, 2002, 80 (01) :27-34
[6]   Human lactoferrin interacts with soluble CD14 and inhibits expression of endothelial adhesion molecules, E-selectin and ICAM-1, induced by the CD14-lipopolysaccharide complex [J].
Baveye, S ;
Elass, E ;
Fernig, DG ;
Blanquart, C ;
Mazurier, J ;
Legrand, D .
INFECTION AND IMMUNITY, 2000, 68 (12) :6519-6525
[7]   Lactoferrin: A multifunctional glycoprotein involved in the modulation of the inflammatory process [J].
Baveye, S ;
Elass, E ;
Mazurier, J ;
Spik, G ;
Legrand, D .
CLINICAL CHEMISTRY AND LABORATORY MEDICINE, 1999, 37 (03) :281-286
[8]  
BENNETT TA, 2001, ANGIOGENESIS HLTH DI, P29
[9]  
BEZAULT J, 1994, CANCER RES, V54, P2310
[10]   LACTOFERRIN - A MULTIFUNCTIONAL IMMUNOREGULATORY PROTEIN [J].
BROCK, J .
IMMUNOLOGY TODAY, 1995, 16 (09) :417-419