Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation.
BACKGROUND
Placental growth factor (PlGF) has been implicated in the pathophysiological angiogenesis and monocyte recruitment that underlie chronic inflammatory disease, but its role in atherosclerosis has not been examined. We investigated the effects of exogenous PlGF, delivered by adenoviral gene transfer, on atherogenic intimal thickening and macrophage accumulation induced by collar placement around the rabbit carotid artery and examined the effects of PlGF deficiency on atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice.


RESULTS
Periadventitial transfer of PlGF2-encoding adenoviruses significantly increased intimal thickening, macrophage accumulation, endothelial vascular cell adhesion molecule-1 expression, and adventitial neovascularization in the collared arteries of hypercholesterolemic rabbits and increased the intima-to-media ratio in rabbits fed a normal diet. Neointimal macrophages were associated with increased expression of the PlGF receptor Flt-1. The size and macrophage content of early atherosclerotic lesions were reduced in mice deficient in both apoE and PlGF compared with apoE-deficient mice.


CONCLUSIONS
Local adenoviral PlGF2 delivery promotes atherogenic neointima formation in hypercholesterolemic rabbits, and PlGF is required for macrophage infiltration in early atherosclerotic lesions in apoE(-/-) mice. These findings support a novel role for PlGF in the pathogenesis of atherosclerotic disease.
Khurana
Rohit
R
BHF Laboratories, Department of Medicine, University College London, 5 University St, London WC1E 6JJ, United Kingdom.
Moons
Lieve
L
Shafi
Shahida
S
Luttun
Aernout
A
Collen
Désiré
D
Martin
John F
JF
Carmeliet
Peter
P
Zachary
Ian C
IC
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D002340:Carotid Artery Diseases; D002465:Cell Movement; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006937:Hypercholesterolemia / Q000150:complications; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
D001057:Apolipoproteins E; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor