Plaque angiogenesis and plaque vulnerability. Angiogenesis: Potential implications

Transcription

1 ESC Congress August 2011 Paris France Plaque angiogenesis and plaque vulnerability Angiogenesis: Potential implications Johannes Waltenberger, MD, PhD, F.E.S.C. Professor and Chair of Internal Medicine, Cardiology and Angiology Director, Department of Cardiology and Angiology University Hospital Münster Germany

2 DECLARATION OF CONFLICT OF INTEREST none

3 Angiogenesis in the atherosclerotic vessel wall

4 Plaque angiogenesis and plaque vulnerability. Angiogenesis: Potential implications. The presence of Angiogenesis / Vasa Vasorum reflects: - Plaque inflammation - Plaque destabilization (ADAM10) - Plaque progression - Plaque rupture (bleedings) Barger et al., N. Engl. J. Med. 310: , 1984

5 Angiogenic factors upregulated in the atherosclerotic vessel wall plaque inflammation afgf Brogi E, J.Clin.Invest Hughes SE et al., Cardiovasc. Res bfgf Hughes SE, Cardiovasc Res, 1993 Brogi E, J.Clin.Invest Lappalainen L, ATVB 2004 M-CSF Nelken NA, J.Clin.Invest Clinton SK et al., Am.J.Pathol MCP-1 Yla-Herttuala S et al., PNAS, 1991 VEGF-A Inoue M et al., Circulation 1998 Ramos MA et al., ATVB 1998 Chen YX, ATVB 1999 PD-ECGF Ignatescu MC et al., ATVB 1999 Angiopoietin-2 Calvi C et al., ATVB 2004 IL-8 Simoni A et al., Circulation 2000 Wang N et al., J.Biol.Chem. 1996

6 Relationship between neovascularization and the degree of VEGF-positive cell occurrence in atherosclerotic intimas of human coronary arteries VEGF-A Chen et al., ATVB 1999 Loukas et al., unpublished

7 Reduced VEGF protein levels in plaques after in vivo treatment with angiostatin AS Ctrl -- VEGF protein -- Moulton et al., PNAS 100: , 2003

8 Identification of novel VEGFR binding partners using Yeast 2-hybrid technology VEGFR VEGF? Binding partners Yeast-two-hybrid screening: Bait: Prey: intracellular domain of human VEGFR1 or VEGFR2 human placenta cdna library Novel candidates binding to VEGFR1: - Filamin A - Four and a half LIM domain (FHL-2) (unknown) signalling intermediates Cellular effects Novel candidates binding to VEGFR2: - A Disintegrin And Metalloprotease 10 (ADAM10) - Rho GDP Dissociation Inhibitor (Rho GDI) - A Kinase Anchor Protein 13 (AKAP13) Donners et al., Arterioscler Thromb Vasc Biol. 30: , 2010

9 ADAM10 as a novel key mediator of VEGF(R) action involved in angiogenesis and atherosclerosis Atherosclerosis & angiogenesis EC detachment & migration Leukocyte chemotaxis & adhesion soluble mediators VEGF svegfr ADAM10 VEGFR signaling endothelial cell Donners et al., Arterioscler Thromb Vasc Biol. 30: , 2010

10 Detection of ADAM10 in human atherosclerotic plaques early advanced stable Foam cells ruptured Vasa vasorum Donners et al., Arterioscler Thromb Vasc Biol. 30: , 2010

11 VEGF induces VE-cadherin cleavage in HUVEC VE-cadherin cleavage is associated with increased permeability Newly formed vessels are immature and potentially fragile Donners et al., Arterioscler Thromb Vasc Biol. 30: , 2010

12 VEGF in the atherosclerotic vessel wall Relation to plaque progression and rupture adding VEGF endogenous VEGF No evidence for further progression No evidence for plaque unstability Endothelial dysfunction Capillary regression Capillary thrombosis Intraplaque hemorrhage Intraplaque necrosis Inhibiting VEGF

13 (VEGF-dependent) Endothelial Function release from BM ability to home antithrombotic antiapoptotic ability to proliferate ability to migrate antiproliferative for SMCs regulation of permeability NO PGI 2 Waltenberger, Br. J. Cardiol., 2009

14 Activation of the VEGF/VEGFR-system in the vessel wall VEGF EC apoptosis EC trombosis EC function plaque vessels stabilized vascular regression prevented VEGF-Blockade plaque stability Plaque progression plaque stability Plaque rupture

15 COX-2 inhibitors trigger plaque rupture.....but block angiogenesis Cumulative incidence of serious thrombotic events (majority with ACS) in vivo angiogenesis assay Rofecoxib Celecoxib Bresalier et al., N Engl J Med 352; , 2005 Masferrer et al., Cancer Res. 60; , 2000

16 Williams et al., J. Clin. Invest. 105: , 2000 VEGF expression is regulated by COX-2 COX-2 inhibitors reduce VEGF expression

17 VEGF in the atherosclerotic vessel wall Relation to plaque progression and rupture adding VEGF endogenous VEGF No evidence for further progression No evidence for plaque unstability Endothelial dysfunction Capillary regression Capillary thrombosis Intraplaque hemorrhage Intraplaque necrosis Inhibiting VEGF

18 Intraplaque hemorrhage and progression of coronary atheroma Thin-Cap Fibroatheroma Macrophages Glycophorin A Iron vwf Kolodgie et al., N Engl J Med 349: , 2003

19 Ion deposits and plaque progression / rupture Stadler et al., under revision

20 Plaque Angiogenesis: Implications for plaque progression and vulnerability Plaque progression correlates with plaque vulnerability Plaque progression is associated with plaque angiogenesis Plaque angiogenesis is associated with plaque inflammation and with the expression of angiogenic factors Angiogenesis results in potentially fragile neovessels, which are prone to leak and rupture (intraplaque hemorrhage) Inhibition of plaque angiogenesis (Anti-VEGF-Ab, COX-2 inhibitors) is likely to trigger plaque rupture

21 Thanks to... Maastricht and Münster Labs on Exp & Molecular Cardiology Nynke van den Akker Frauke S. Czepluch Marjo Donners Marina Dunaeva Mick Gagliardi Fabienne Jeukens Servé Olieslagers Evangelia Pardali Nadina Stadler Nathalie Stonka Vadim Tchaikovski Fons Verheyen Stefan Vöö Münster Collaborators Ralf Adams Frank U. Müller Andreas H. Jakobs Johannes Roth Michael Schäfers Otmar Schober Hans Schöler Lydia Sorokin Dietmar Vestweber External Collaborators Frank-D Böhmer Kenneth Caidahl Hugo ten Cate Peter Carmeliet Lena Claesson-Welsh Mat Daemen Peter ten Dijke Carl-Henrik Heldin Jens Kroll Tim Leiner Charles Lapière Karl Plate Mark J. Post Frits Prinzen Masabumi Shibuya Marina Ziche Juleen Zierath INTACT 1