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


CONCLUSIONS
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.
Norrby
Klas
K
Department of Pathology, Institute of Laboratory Medicine, Sahlgrenska Academy, Göteborg University, Gothenburg, Sweden.
D000284:Administration, Oral; D000818:Animals; D021461:Animals, Outbred Strains; D001059:Apoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007260:Infusion Pumps; D007279:Injections, Subcutaneous; D007781:Lactoferrin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013152:Splanchnic Circulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D001059:Apoproteins; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C039223:apolactoferrin; C492629:hololactoferrin, human; D016222:Fibroblast Growth Factor 2; D007781:Lactoferrin