Delayed arteriogenesis in hypercholesterolemic mice.
BACKGROUND
Hypercholesterolemia has been reported to inhibit ischemia-induced angiogenesis. To address its effects on arteriogenesis, we investigated arterial growth in hypercholesterolemic low-density lipoprotein receptor(-/-)/ApoB-48(-/-) (HCE) mice.


RESULTS
The extent and the time course of arteriogenesis after femoral artery ligation was evaluated in HCE and strain-matched control mice. Distal limb perfusion was measured by laser Doppler imaging, whereas MRI was used to visualize arterial flow and micro-computed tomography to assess vascular growth. After femoral artery ligation, serial laser Doppler imaging demonstrated significantly delayed restoration of perfusion in untreated HCE compared with control mice (day 3, 0.09 versus 0.19, P<0.05). Treatment with Ad-PR39 in control mice led to a significant restoration of arterial blood flow and tissue perfusion at day 3, whereas in HCE mice, hindlimb perfusion began increasing only by day 7. Micro-CT analysis confirmed increased growth of smaller arterioles (16 to 63 microm in diameter) in the Ad-PR39-treated control compared with HCE mice. The delay in arteriogenesis in HCE mice correlated with delayed tissue appearance of F4/80+ cells. Analysis of gene expression after Ad-PR39 treatment demonstrated that HCE mice had significantly reduced expression of FGF receptor 1, hypoxia-inducible factor-1alpha, vascular cell adhesion molecule-1, macrophage scavenger receptor-1, and cyclophilin A compared with controls 3 days after arterial ligation that equalized by day 7, mimicking relative changes in arteriogenesis and tissue perfusion.


CONCLUSIONS
Hypercholesterolemia results in delayed native arteriogenesis because of reduced early monocyte/macrophage influx and delayed and impaired arterial growth response to growth factor therapy.
Tirziu
Daniela
D
Angiogenesis Research Center, Department of Medicine, Dartmouth Medical School, Lebanon, NH, USA.
Moodie
Karen L
KL
Zhuang
Zhen W
ZW
Singer
Katie
K
Helisch
Armin
A
Dunn
Jeff F
JF
Li
Weiming
W
Singh
Jaipal
J
Simons
Michael
M
D000818:Animals; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D001783:Blood Flow Velocity; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology; D005263:Femoral Artery / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007511:Ischemia / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014471:Umbilical Veins / Q000502:physiology
D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; D011973:Receptors, LDL