GM-CSF: a strong arteriogenic factor acting by amplification of monocyte function.
We investigated the role of the colony stimulating factor for monocytes (GM-CSF) to test the hypothesis whether prolongation of the monocyte's life cycle will support arteriogenesis (rapid growth of preexisting collateral arteries). This appeared logical in view of our discovery that circulating monocytes play an important part in the positive remodeling of small preexisting arterioles into arteries to compensate for arterial occlusions (arteriogenesis) and especially following our findings that MCP-1 markedly increases the speed of arteriogenesis. The continuous infusion of GM-CSF for 7 days into the proximal stump of the acutely occluded femoral artery of rabbits by osmotic minipump produced indeed a marked arteriogenic response as demonstrated by an increase (2-fold) in number and size of collateral arteries on postmortem angiograms and by the increase of maximal blood flow during vasodilation measured in vivo by blood pump perfusion of the hindquarter (5-fold). When GM-CSF and MCP-1 were simultaneously infused the effects on arteriogenesis were additive on angiograms as well as on conductance. GM-CSF was also able to widen the time window of MCP-1 activity: MCP-1 treatment alone was ineffective when given after the third week following occlusion. When administered together with GM-CSF about 80% of normal maximal conductance of the artery that was replaced by collaterals were achieved, a result that was not reached before by any other experimental treatment. Experiments with cells isolated from treated animals showed that monocyte apoptosis was markedly reduced. In addition we hypothesize that GM-CSF may aid in releasing pluripotent monocyte (stem-) cells from the bone marrow into the circulation. In contrast to MCP-1, GM-CSF showed no activity on monocyte transmigration through- and also no influence on monocyte adhesion to cultured endothelial cells. In conclusion we have discovered a new function of the hemopoietic stem cell factor GM-CSF, which is also a powerful arteriogenic peptide that acts via prolongation of the life cycle of monocytes/macrophages.
Buschmann
I R
IR
Research Group for Experimental and Clinical Arteriogenesis at the Department of Cardiology and Angiology, Albert Ludwigs University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany. buschmann@med1.ukl.uni-freiburg.de
Hoefer
I E
IE
van Royen
N
N
Katzer
E
E
Braun-Dulleaus
R
R
Heil
M
M
Kostin
S
S
Bode
C
C
Schaper
W
W
D000792:Angiography; D000818:Animals; D017209:Apoptosis; D001157:Arterial Occlusive Diseases / Q000188:drug therapy*; D018932:Chemokine CCL2 / Q000494:pharmacology*; D003097:Collateral Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005263:Femoral Artery; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008074:Lipoproteins / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D011336:Probability; D011817:Rabbits; D018709:Statistics, Nonparametric
D018932:Chemokine CCL2; D008074:Lipoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor