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Placenta growth factor expression in human atherosclerotic carotid plaques is related to plaque destabilization

      Abstract

      Background and purpose

      Placenta growth factor (PlGF) mediates angiogenesis and inflammation, but its role in human atherosclerosis is unknown. This study was designed to test the hypothesis that PlGF-expression in human atherosclerotic carotid plaques is related to inflammation, vascularization and clinical plaque instability.

      Methods

      The expression of PlGF, C-reactive protein (CRP) and CD40L was analyzed with Western blots in carotid plaques of 60 patients. Cellular infiltration (CD68, CD3) and vascularization (von-Willebrand-factor) was assessed by immunohistochemistry.

      Results

      Symptomatic patients showed higher levels of PlGF than asymptomatic patients (115.4 ± 8.2 versus 83.6 ± 10.5 densitometric units (DU), p < 0.05) and higher grading for inflammatory cells and microvessels (CD3: 2.3 ± 0.1 versus 0.6 ± 0.1, p < 0.001, CD68: 2.4 ± 0.1 versus 0.8 ± 0.1, p < 0.001, microvessels: 2.3 ± 0.1 versus 1.5 ± 0.1, p < 0.01). PlGF-expression showed a positive correlation to the expression of CRP (r = 0.5, p < 0.001) and CD40L (r = 0.4, p < 0.01).

      Conclusions

      PlGF-expression within human atherosclerotic lesions is associated with plaque inflammation and microvascular density, suggesting a role for PlGF in plaque destabilization and, thus, in clinical manifestation of the disease.

      Keywords

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      References

        • Ross R.
        Atherosclerosis—an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Carr S.
        • Farb A.
        • Pearce W.H.
        • Virmani R.
        • Yao J.S.
        Atherosclerotic plaque rupture in symptomatic carotid artery stenosis.
        J Vasc Surg. 1996; 23: 755-765
        • Fleiner M.
        • Kummer M.
        • Mirlacher M.
        • et al.
        Arterial neovascularization and inflammation in vulnerable patients: early and late signs of symptomatic atherosclerosis.
        Circulation. 2004; 110: 2843-2850
        • Moreno P.R.
        • Purushothaman K.R.
        • Fuster V.
        • et al.
        Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta: implications for plaque vulnerability.
        Circulation. 2004; 110: 2032-2038
        • Mofidi R.
        • Crotty T.B.
        • McCarthy P.
        • et al.
        Association between plaque instability, angiogenesis and symptomatic carotid occlusive disease.
        Br J Surg. 2001; 88: 945-950
        • Loftus I.M.
        • Naylor A.R.
        • Goodall S.
        • et al.
        Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption.
        Stroke. 2000; 31: 40-47
        • Shah P.K.
        • Falk E.
        • Badimon J.J.
        • et al.
        Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture.
        Circulation. 1995; 92: 1565-1569
        • Lutgens E.
        • Daemen M.J.
        CD40-CD40L interactions in atherosclerosis.
        Trends Cardiovasc Med. 2002; 12: 27-32
        • Yeh E.T.
        CRP as a mediator of disease.
        Circulation. 2004; 109 (II 11-II 14)
        • Verma S.
        • Devaraj S.
        • Jialal I.
        Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis.
        Circulation. 2006; 113: 2135-2150
        • Venugopal S.K.
        • Devaraj S.
        • Yuhanna I.
        • Shaul P.
        • Jialal I.
        Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells.
        Circulation. 2002; 106: 1439-1441
        • Lin R.
        • Liu J.
        • Gan W.
        • Yang G.
        C-reactive protein-induced expression of CD40–CD40L and the effect of lovastatin and fenofibrate on it in human vascular endothelial cells.
        Biol Pharm Bull. 2004; 27: 1537-1543
        • Schonbeck U.
        • Mach F.
        • Libby P.
        CD154 (CD40 ligand).
        Int J Biochem Cell Biol. 2000; 32: 687-693
        • Mach F.
        • Schonbeck U.
        • Sukhova G.K.
        • Atkinson E.
        • Libby P.
        Reduction of atherosclerosis in mice by inhibition of CD40 signalling.
        Nature. 1998; 394: 200-203
        • Donnini S.
        • Machein M.R.
        • Plate K.H.
        • Weich H.A.
        Expression and localization of placenta growth factor and PlGF receptors in human meningiomas.
        J Pathol. 1999; 189: 66-71
        • Matsumoto K.
        • Suzuki K.
        • Koike H.
        • et al.
        Placental growth factor gene expression in human prostate cancer and benign prostate hyperplasia.
        Anticancer Res. 2003; 23: 3767-3773
        • Perelman N.
        • Selvaraj S.K.
        • Batra S.
        • et al.
        Placenta growth factor activates monocytes and correlates with sickle cell disease severity.
        Blood. 2003; 102: 1506-1514
        • Carmeliet P.
        • Moons L.
        • Luttun A.
        • et al.
        Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.
        Nat Med. 2001; 7: 575-583
        • Sattler K.J.
        • Woodrum J.E.
        • Galili O.
        • et al.
        Concurrent treatment with renin-angiotensin system blockers and acetylsalicylic acid reduces nuclear factor kappaB activation and C-reactive protein expression in human carotid artery plaques.
        Stroke. 2005; 36: 14-20
        • Rodriguez-Porcel M.
        • Lerman L.O.
        • Holmes Jr., D.R.
        • et al.
        Chronic antioxidant supplementation attenuates nuclear factor-kappa B activation and preserves endothelial function in hypercholesterolemic pigs.
        Cardiovasc Res. 2002; 53: 1010-1018
        • Zhu X.Y.
        • Rodriguez-Porcel M.
        • Bentley M.D.
        • et al.
        Antioxidant intervention attenuates myocardial neovascularization in hypercholesterolemia.
        Circulation. 2004; 109: 2109-2115
        • Sawano A.
        • Takahashi T.
        • Yamaguchi S.
        • Aonuma M.
        • Shibuya M.
        Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor.
        Cell Growth Differ. 1996; 7: 213-221
        • Neufeld G.
        • Kessler O.
        • Herzog Y.
        The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors for VEGF.
        Adv Exp Med Biol. 2002; 515: 81-90
        • Clauss M.
        • Weich H.
        • Breier G.
        • et al.
        The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis.
        J Biol Chem. 1996; 271: 17629-17634
        • Clauss M.
        Functions of the VEGF receptor-1 (FLT-1) in the vasculature.
        Trends Cardiovasc Med. 1998; 8: 241-245
        • Rohde L.E.
        • Lee R.T.
        Pathophysiology of atherosclerotic plaque development and rupture: an overview.
        Semin Vasc Med. 2003; 3: 347-354
        • Sitzer M.
        • Muller W.
        • Siebler M.
        • et al.
        Plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis.
        Stroke. 1995; 26: 1231-1233
        • Schonbeck U.
        • Mach F.
        • Sukhova G.K.
        • et al.
        Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture?.
        Circ Res. 1997; 81: 448-454
        • Mach F.
        • Schonbeck U.
        • Bonnefoy J.Y.
        • Pober J.S.
        • Libby P.
        Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor.
        Circulation. 1997; 96: 396-399
        • Khurana R.
        • Moons L.
        • Shafi S.
        • et al.
        Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation.
        Circulation. 2005; 111: 2828-2836
        • Luttun A.
        • Tjwa M.
        • Moons L.
        • et al.
        Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1.
        Nat Med. 2002; 8: 831-840
        • Heeschen C.
        • Dimmeler S.
        • Fichtlscherer S.
        • et al.
        CAPTURE Investigators. Prognostic value of placental growth factor in patients with acute chest pain.
        JAMA. 2004; 291: 435-441
        • Bisoendial R.J.
        • Kastelein J.J.
        • Levels J.H.
        • et al.
        Activation of inflammation and coagulation after infusion of C-reactive protein in humans.
        Circ Res. 2005; 96: 714-716
        • Verma S.
        • Li S.H.
        • Badiwala M.V.
        • et al.
        Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein.
        Circulation. 2002; 105: 1890-1896
        • Torzewski M.
        • Rist C.
        • Mortensen R.F.
        • et al.
        C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis.
        Arterioscler Thromb Vasc Biol. 2000; 20: 2094-2099
        • Schonbeck U.
        • Libby P.
        CD40 signaling and plaque instability.
        Circ Res. 2001; 89: 1092-1103
        • Kotowicz K.
        • Dixon G.L.
        • Klein N.J.
        • Peters M.J.
        • Callard R.E.
        Biological function of CD40 on human endothelial cells: costimulation with CD40 ligand and interleukin-4 selectively induces expression of vascular cell adhesion molecule-1 and P-selectin resulting in preferential adhesion of lymphocytes.
        Immunology. 2000; 100: 441-448
        • Slupsky J.R.
        • Kalbas M.
        • Willuweit A.
        • et al.
        Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40.
        Thromb Haemost. 1998; 80: 1008-1014
        • May A.E.
        • Kalsch T.
        • Massberg S.
        • et al.
        Engagement of glycoprotein IIb/IIIa (alpha(IIb)beta3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells.
        Circulation. 2002; 106: 2111-2117
        • Larsson A.
        • Hansson L.O.
        High sensitivity CRP and serum amyloid A as expressions of low grade inflammation do not correlate with bFGF or VEGF.
        Ups J Med Sci. 2003; 108: 51-59
        • Krupinski J.
        • Turu M.M.
        • Martinez-Gonzalez J.
        • et al.
        Endogenous expression of C-reactive protein is increased in active (ulcerated noncomplicated) human carotid artery plaques.
        Stroke. 2006; 37: 1200-1204
        • McCarthy M.J.
        • Loftus I.M.
        • Thompson M.M.
        • et al.
        Angiogenesis and the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology.
        J Vasc Surg. 1999; 30: 261-268
        • Costa C.
        • Soares R.
        • Schmitt F.
        Angiogenesis: now and then.
        APMIS. 2004; 112: 402-412