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(Circulation. 2005;111:2828-2836.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Placental Growth Factor Promotes Atherosclerotic Intimal Thickening and Macrophage Accumulation

Rohit Khurana, MD^*; Lieve Moons, PhD^*; Shahida Shafi, PhD; Aernout Luttun, PhD; Désiré Collen, MD, PhD; John F. Martin, FRCP; Peter Carmeliet, MD, PhD^*; Ian C. Zachary, PhD^*

From BHF Laboratories (R.K., S.S., J.F.M., I.C.Z.), Department of Medicine, University College London, London, United Kingdom, and Center for Transgene Technology & Gene Therapy (L.M., A.L., D.C., P.C.), University of Leuven, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.

Correspondence to Ian C. Zachary, PhD, BHF Laboratories, Department of Medicine, The Rayne Building, University College London, 5 University St, London WC1E 6JJ, United Kingdom. E-mail I.Zachary{at}ucl.ac.uk

Received July 29, 2004; revision received December 23, 2004; accepted January 25, 2005.

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.

Methods and 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.

Key Words: angiogenesis • atherosclerosis • cell adhesion molecules • endothelium • monocytes

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