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Cardiovascular Research Advance Access first published online on July 20, 2009
This version [Corrected Proof] published online on August 13, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp253
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Immaturity of microvessels in haemorrhagic plaques is associated with proteolytic degradation of angiogenic factors

Julien Le Dall1, Benoît Ho-Tin-Noé1, Liliane Louedec1, Olivier Meilhac1, Carmen Roncal2, Peter Carmeliet2, Stéphane Germain3,4,5, Jean-Baptiste Michel1,* and Xavier Houard1

1 Inserm and Univ. Paris 7, Research Unit 698, Cardiovascular Haematology, Bio-Engineering and Remodelling, Bichat-Claude Bernard Hospital, 46, rue Henri Huchard, F-75877 Paris Cedex 18, France
2 Vesalius Research Center, VIB, 3000 Leuven, Belgium
3 Inserm, U833, Embryonic and Pathological Angiogenesis, F-75005 Paris, France
4 Collège de France, F-75005 Paris, France
5 Service d'Hématologie Biologique A-AP-HP-Hôpital Européen Georges Pompidou, F-75015 Paris, France

* Corresponding author. Tel: +33 1 402 58 600, Fax: +33 1 402 58 602, Email: jean-baptiste.michel{at}inserm.fr

Aims: We investigated the causes of microvessel immaturity and destabilization in human atherosclerotic lesions.

Methods and results: Human atherosclerotic carotid plaques (n = 24) were classified as non-haemorrhagic (NH) or haemorrhagic (Hem), according to their macroscopic aspect and haemoglobin content. Plaque microvessel density and maturity were quantified by immunohistochemistry. Expression of angiogenic factors was studied by immunohistochemistry, in situ hybridization, and ELISA. Plaque-conditioned media were tested for plasmin and elastase activities and for their ability to degrade angiogenic factors and to induce smooth muscle cell migration. Microvessel density and leucocyte infiltration were increased in Hem compared with NH plaques. Plaque vasculature appeared vulnerable as indicated by the absence of {alpha}-actin-positive mural cells in most plaque vessels. Despite increased numbers of angiogenic factor-expressing microvessels and leucocytes in Hem plaques, lower levels of vascular endothelial growth factor, placental growth factor, and angiopoietin-1 were found in conditioned media from Hem plaques. However, NH and Hem plaques released similar levels of the vascular destabilizing factor, angiopoietin-2. Addition of recombinant angiogenic factors to plaque extracts showed that all factors but angiopoietin-2 were selectively degraded by plasmin and/or elastase released from Hem plaques. Furthermore, conditioned media from Hem plaques showed a reduced ability to induce smooth muscle cell migration.

Conclusion: Our results provide evidence that immaturity of plaque vessels is associated with the degradation of angiogenic factors by haemorrhage-conveyed leucocytes and proteases.

KEYWORDS Angiogenesis; VEGF; Angiopoietins; Plasmin

Time for primary review: 25 days


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