Metallothionein enhances angiogenesis and arteriogenesis by modulating smooth muscle cell and macrophage function.
OBJECTIVE
In a previous study we identified metallothionein (MT) as a candidate gene potentially influencing collaterogenesis. In this investigation, we determined the effect of MT on collaterogenesis and examined the mechanisms contributing to the effects we found.


RESULTS
Collateral blood flow recovery was assessed using laser Doppler perfusion imaging, and angiogenesis was measured using a Matrigel plug assay. Smooth muscle cells were isolated from MT knockout (KO) mice for functional assays. Gene expression of matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, and Fat cadherin in smooth muscle cells was measured by real-time polymerase chain reaction, and protein levels of vascular endothelial growth factor and matrix metalloproteinase-9 were determined using enzyme-linked immunosorbent assay and Western blot. CD11b(+) macrophages were tested for invasiveness using a real-time impedance assay. Both flow recovery and angiogenesis were impaired in MT KO mice. Proliferation, migration, and invasion were decreased in MT KO smooth muscle cells, and matrix metalloproteinase-9, platelet-derived growth factor, and vascular endothelial growth factor expression were also decreased, whereas FAT-1 cadherin expression was elevated. MT KO CD11b(+) cells were more invasive than wild-type cells.


CONCLUSIONS
MT plays an important role in collateral flow recovery and angiogenesis, an activity that appears to be mediated, in part, by the effects of MT on the functionality of 3 cell types essential for these processes: endothelial cells, smooth muscle cells, and macrophages.
Zbinden
Stephan
S
Cardiovascular Research Institute, MedStar Research Institute, 108 Irving Street, NW, Room 214, Washington, DC 20010, USA.
Wang
Jinsong
J
Adenika
Remi
R
Schmidt
Marcel
M
Tilan
Justin U
JU
Najafi
Amir H
AH
Peng
Xinzhi
X
Lassance-Soares
Roberta M
RM
Iantorno
Micaela
M
Morsli
Hakim
H
Gercenshtein
Leonid
L
Jang
Gil Jin
GJ
Epstein
Stephen E
SE
Burnett
Mary Susan
MS
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000254:growth & development*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology
D008668:Metallothionein