Published Online
on May 23, 2005

A more recent version of this article appeared on May 31, 2005

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Submitted on July 29, 2004
Revised on December 23, 2004
Accepted on January 25, 2005

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, and 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.

^* To whom correspondence should be addressed. E-mail: I.Zachary{at}ucl.ac.uk.

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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