This Article Full Text Full Text (PDF) All Versions of this Article: 111/21/2828    most recent CIRCULATIONAHA.104.495887v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khurana, R. Articles by Zachary, I. C. Search for Related Content PubMed PubMed Citation Articles by Khurana, R. Articles by Zachary, I. C. Related Collections Angiogenesis Pathophysiology Genetically altered mice Growth factors/cytokines

(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

This article has been cited by other articles:

				J. C. Sluimer, F. D. Kolodgie, A. P.J.J. Bijnens, K. Maxfield, E. Pacheco, B. Kutys, H. Duimel, P. M. Frederik, V. W.M. van Hinsbergh, R. Virmani, et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage. J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1517 - 1527. [Abstract] [Full Text] [PDF]

				A. Cassidy, S. E. Chiuve, J. E. Manson, K. M. Rexrode, C. J. Girman, and E. B. Rimm Potential Role for Plasma Placental Growth Factor in Predicting Coronary Heart Disease Risk in Women Arterioscler Thromb Vasc Biol, January 1, 2009; 29(1): 134 - 139. [Abstract] [Full Text] [PDF]

				K. Yano, Y. Okada, G. Beldi, S.-C. Shih, N. Bodyak, H. Okada, P. M. Kang, W. Luscinskas, S. C. Robson, P. Carmeliet, et al. Elevated levels of placental growth factor represent an adaptive host response in sepsis J. Exp. Med., October 27, 2008; 205(11): 2623 - 2631. [Abstract] [Full Text] [PDF]

				W. Koenig and N. Khuseyinova Biomarkers of Atherosclerotic Plaque Instability and Rupture Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 15 - 26. [Abstract] [Full Text] [PDF]

				L. Xu, D. M. Cochran, R. T. Tong, F. Winkler, S. Kashiwagi, R. K. Jain, and D. Fukumura Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res., April 15, 2006; 66(8): 3971 - 3977. [Abstract] [Full Text] [PDF]

				R. Khurana, M. Simons, J. F. Martin, and I. C. Zachary Role of Angiogenesis in Cardiovascular Disease: A Critical Appraisal Circulation, September 20, 2005; 112(12): 1813 - 1824. [Abstract] [Full Text] [PDF]