The role of angiogenic growth factors in arteriogenesis.
OBJECTIVE
Collateral vessels restore only about 40% of the maximum dilatory reserve after femoral artery occlusion, whereas complete normalization is reached by increased fluid shear stress (FSS). We studied the role of known potent angiogenic growth factors (separately or in combination) in arteriogenesis by determining their expression in FSS-stimulated collaterals and close-to-collateral infusion of growth factor peptides in a rabbit model of femoral artery occlusion.


METHODS
Values of maximum collateral conductance (C(max)) and post mortem angiograms were compared to those achievable by high FSS. mRNA levels of growth factor ligands and receptors were determined in FSS-stimulated collaterals.


RESULTS
Seven days after vessel occlusion, FSS-stimulated legs showed a C(max) not significantly different from that of not occluded femoral arteries. Arteriogenesis was significantly less enhanced after growth factor treatment (MCP-1 86%, Ad5.1-FGF-4 75%, bFGF 72%, PDGF 64%, VEGF 50% of C(max) after FSS stimulation). RT-PCR showed no differential expression of FGF receptors, but an up-regulation of VEGF-receptor-2.


CONCLUSIONS
The most potent known angiogenic growth factors at high pharmacological doses reach only a fraction of the maximum conductance obtained by high FSS. Arteriogenesis differs from angiogenesis, so the main focus to markedly improve arteriogenesis should be put on the underlying mechanisms of shear stress.
Schierling
Wilma
W
Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Troidl
Kerstin
K
Troidl
Christian
C
Schmitz-Rixen
Thomas
T
Schaper
Wolfgang
W
Eitenmüller
Inka K
IK
D042501:Angiogenic Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001166:Arteriovenous Shunt, Surgical; D018932:Chemokine CCL2 / Q000378:metabolism; D003097:Collateral Circulation / Q000235:genetics; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D018056:Hemorheology; D007260:Infusion Pumps; D008026:Ligation; D008297:Male; D018919:Neovascularization, Physiologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042501:Angiogenic Proteins; D018932:Chemokine CCL2; C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2