Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma.
BACKGROUND
Although multiple pathological processes have been associated with oxidative stress, the causative relation between oxidative stress and arterial lesion progression remains unclear.


RESULTS
To test the effect of creating arterial wall oxidative stress, we compared progression of mouse carotid lesions induced by flow cessation in the wild-type (WT) versus transgenic mice (Tg(p22vsmc)), in which overexpression of p22phox, a critical component of NAD(P)H oxidase was targeted to smooth muscle cell (SMC). Compared with WT mice, arterial lesions grew significantly larger in Tg(p22vsmc) (P<0.001) and demonstrated elevated hydrogen peroxide (H2O2) and vascular endothelial growth factor (VEGF) levels at all time points examined (P<0.001, n=4 animals per time point), probably related to increased expression of hypoxia inducible factor (HIF)-1alpha via SMC oxidative stress in the Tg(p22vsmc) arteries, both basally (203+/-12% versus WT, P<0.001, n=3) and after lesion formation. Interestingly, Tg(p22vsmc) lesions were complicated by extensive neointimal angiogenesis. In vitro experiments confirmed SMCs isolated from Tg(p22vsmc) to be the source for increased H2O2, VEGF, and HIF-1alpha and their capacity to induce angiogenic cord-like structures when cocultured with endothelial cells. The antioxidant ebselen inhibited SMC activities in vitro and intralesion angiogenesis and lesion progression in vivo.


CONCLUSIONS
We have demonstrated a novel pathway by which oxidative stress can trigger in vivo an angiogenic switch associated with experimental plaque progression and angiogenesis. This pathway may be related to human atheroma progression and destabilization through intraplaque hemorrhage.
Khatri
Jaikirshan J
JJ
Division of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Johnson
Chad
C
Magid
Richard
R
Lessner
Susan M
SM
Laude
Karine M
KM
Dikalov
Sergey I
SI
Harrison
David G
DG
Sung
Hak-Joon
HJ
Rong
Yuan
Y
Galis
Zorina S
ZS
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D001393:Azoles / Q000494:pharmacology; D002340:Carotid Artery Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D006861:Hydrogen Peroxide / Q000378:metabolism; D054833:Isoindoles; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009252:NADPH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000473:pathology; D016566:Organoselenium Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D026901:Membrane Transport Proteins; D016566:Organoselenium Compounds; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C042986:ebselen; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase