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A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation.

Massberg S, Brand K, Grüner S, Page S, Müller E, Müller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M - J. Exp. Med. (2002)

Bottom Line: Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE(-)(/)(-) mice before the development of manifest atherosclerotic lesions.Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes.Prolonged blockade of platelet adhesion in ApoE(-)(/)(-) mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries.

View Article: PubMed Central - PubMed

Affiliation: Deutsches Herzzentrum und 1. Medizinische Klinik, Technische Universität München, Germany. massberg@dhm.mhn.de

ABSTRACT
The contribution of platelets to the process of atherosclerosis remains unclear. Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE(-)(/)(-) mice before the development of manifest atherosclerotic lesions. Platelet-endothelial cell interaction involved both platelet glycoprotein (GP)Ibalpha and GPIIb-IIIa. Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes. Prolonged blockade of platelet adhesion in ApoE(-)(/)(-) mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries. These findings establish the platelet as a major player in initiation of the atherogenetic process.

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Reduction of atherosclerotic lesion formation after inhibition of platelet adhesion by anti-GPIbα treatment. (A) Vascular resistance index (RI) was analyzed by color duplex sonography. Mean ± SEM of 4–6 experiments per group; *P < 0.05. (B) The extension of fatty streaks (μm2) was quantified in common carotid of ApoE−/− mice by Sudan III staining in anti–GPIbα-treated mice and untreated or rat IgG-treated control animals. Data represent mean values with SEM (4–6 experiments per group) of 18-wk-old ApoE−/− mice treated 12 wk with anti-GPIbα mAb. *P < 0.05. (C) Cross-sectional plaque area was assessed on 20 serial section of the common carotid artery adjacent to the carotid bifurcation and was evaluated for each animal as the difference between the area, delimited by the internal elastic lamina, and the lumen area. The results were normalized to total vessel cross-sectional area to eliminate variations due to vessel size. Data represent mean values with SEM (4–6 experiments per group) of ApoE−/− mice treated for 12 wk with anti-GPIbα mAb. *P < 0.05. Representative sections (original magnification: 200-fold) stained with elastica van Giesson reagent are presented in D. ACC, common carotid artery; ACE, external carotid artery, ACI, internal carotid artery. (E) Role of platelet adhesion for atherosclerotic lesion formation in the aortic sinus (top panel) and the right and left main coronary arteries (bottom panel, plaque area is presented as percentage of total cross-sectional intimal area). 18-wk-old ApoE−/− mice were treated with vehicle (Control), irrelevant rat IgG, or anti-GPIbα mAb for 12 wk. Atherosclerotic lesion formation was assessed in the aortic sinus and the proximal coronary arteries. Inhibition of platelet adhesion induced a significant reduction in atherosclerotic lesion formation in the aortic sinus and the proximal coronary arteries. Aortic plaque area is presented in μm2; coronary plaque area is given as percentage of the area delimited by the internal elastic lamina (intimal area). Mean ± SEM, P < 0.05 versus Control. Representative histological sections of the aortic sinus and the coronary arteries stained with elastica van Giesson reagent are presented in F and G, respectively (original magnification: 200-fold).
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fig4: Reduction of atherosclerotic lesion formation after inhibition of platelet adhesion by anti-GPIbα treatment. (A) Vascular resistance index (RI) was analyzed by color duplex sonography. Mean ± SEM of 4–6 experiments per group; *P < 0.05. (B) The extension of fatty streaks (μm2) was quantified in common carotid of ApoE−/− mice by Sudan III staining in anti–GPIbα-treated mice and untreated or rat IgG-treated control animals. Data represent mean values with SEM (4–6 experiments per group) of 18-wk-old ApoE−/− mice treated 12 wk with anti-GPIbα mAb. *P < 0.05. (C) Cross-sectional plaque area was assessed on 20 serial section of the common carotid artery adjacent to the carotid bifurcation and was evaluated for each animal as the difference between the area, delimited by the internal elastic lamina, and the lumen area. The results were normalized to total vessel cross-sectional area to eliminate variations due to vessel size. Data represent mean values with SEM (4–6 experiments per group) of ApoE−/− mice treated for 12 wk with anti-GPIbα mAb. *P < 0.05. Representative sections (original magnification: 200-fold) stained with elastica van Giesson reagent are presented in D. ACC, common carotid artery; ACE, external carotid artery, ACI, internal carotid artery. (E) Role of platelet adhesion for atherosclerotic lesion formation in the aortic sinus (top panel) and the right and left main coronary arteries (bottom panel, plaque area is presented as percentage of total cross-sectional intimal area). 18-wk-old ApoE−/− mice were treated with vehicle (Control), irrelevant rat IgG, or anti-GPIbα mAb for 12 wk. Atherosclerotic lesion formation was assessed in the aortic sinus and the proximal coronary arteries. Inhibition of platelet adhesion induced a significant reduction in atherosclerotic lesion formation in the aortic sinus and the proximal coronary arteries. Aortic plaque area is presented in μm2; coronary plaque area is given as percentage of the area delimited by the internal elastic lamina (intimal area). Mean ± SEM, P < 0.05 versus Control. Representative histological sections of the aortic sinus and the coronary arteries stained with elastica van Giesson reagent are presented in F and G, respectively (original magnification: 200-fold).

Mentions: Strikingly, inhibition of platelet adhesion (for 12 wk) significantly reduced the increase in vascular resistance index in 18-wk-old ApoE−/− mice, when compared with untreated 18-wk-old animals (Fig. 4 A, P < 0.05). Furthermore, the anti-GPIbα treatment dramatically limited atherosclerotic lesion formation as compared with control animals. Quantitative computer-assisted image analysis showed an ∼90% reduction in the extent of fatty streak formation in 18-wk-old ApoE−/− mice treated with anti-GPIbα mAb for 12 wk, as assessed by Sudan III staining (Fig. 4 B). Moreover, anti–GPIbα-treated ApoE−/− mice showed substantial decreases in cross-sectional carotid plaque area (by 81%, P < 0.05) (Fig. 4 C). In contrast, in ApoE−/− mice, treated with isotype-matched control rat IgG, atheroprogression in the carotid artery was neither accelerated nor retarded, when compared with untreated ApoE−/− mice.


A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation.

Massberg S, Brand K, Grüner S, Page S, Müller E, Müller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M - J. Exp. Med. (2002)

Reduction of atherosclerotic lesion formation after inhibition of platelet adhesion by anti-GPIbα treatment. (A) Vascular resistance index (RI) was analyzed by color duplex sonography. Mean ± SEM of 4–6 experiments per group; *P < 0.05. (B) The extension of fatty streaks (μm2) was quantified in common carotid of ApoE−/− mice by Sudan III staining in anti–GPIbα-treated mice and untreated or rat IgG-treated control animals. Data represent mean values with SEM (4–6 experiments per group) of 18-wk-old ApoE−/− mice treated 12 wk with anti-GPIbα mAb. *P < 0.05. (C) Cross-sectional plaque area was assessed on 20 serial section of the common carotid artery adjacent to the carotid bifurcation and was evaluated for each animal as the difference between the area, delimited by the internal elastic lamina, and the lumen area. The results were normalized to total vessel cross-sectional area to eliminate variations due to vessel size. Data represent mean values with SEM (4–6 experiments per group) of ApoE−/− mice treated for 12 wk with anti-GPIbα mAb. *P < 0.05. Representative sections (original magnification: 200-fold) stained with elastica van Giesson reagent are presented in D. ACC, common carotid artery; ACE, external carotid artery, ACI, internal carotid artery. (E) Role of platelet adhesion for atherosclerotic lesion formation in the aortic sinus (top panel) and the right and left main coronary arteries (bottom panel, plaque area is presented as percentage of total cross-sectional intimal area). 18-wk-old ApoE−/− mice were treated with vehicle (Control), irrelevant rat IgG, or anti-GPIbα mAb for 12 wk. Atherosclerotic lesion formation was assessed in the aortic sinus and the proximal coronary arteries. Inhibition of platelet adhesion induced a significant reduction in atherosclerotic lesion formation in the aortic sinus and the proximal coronary arteries. Aortic plaque area is presented in μm2; coronary plaque area is given as percentage of the area delimited by the internal elastic lamina (intimal area). Mean ± SEM, P < 0.05 versus Control. Representative histological sections of the aortic sinus and the coronary arteries stained with elastica van Giesson reagent are presented in F and G, respectively (original magnification: 200-fold).
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fig4: Reduction of atherosclerotic lesion formation after inhibition of platelet adhesion by anti-GPIbα treatment. (A) Vascular resistance index (RI) was analyzed by color duplex sonography. Mean ± SEM of 4–6 experiments per group; *P < 0.05. (B) The extension of fatty streaks (μm2) was quantified in common carotid of ApoE−/− mice by Sudan III staining in anti–GPIbα-treated mice and untreated or rat IgG-treated control animals. Data represent mean values with SEM (4–6 experiments per group) of 18-wk-old ApoE−/− mice treated 12 wk with anti-GPIbα mAb. *P < 0.05. (C) Cross-sectional plaque area was assessed on 20 serial section of the common carotid artery adjacent to the carotid bifurcation and was evaluated for each animal as the difference between the area, delimited by the internal elastic lamina, and the lumen area. The results were normalized to total vessel cross-sectional area to eliminate variations due to vessel size. Data represent mean values with SEM (4–6 experiments per group) of ApoE−/− mice treated for 12 wk with anti-GPIbα mAb. *P < 0.05. Representative sections (original magnification: 200-fold) stained with elastica van Giesson reagent are presented in D. ACC, common carotid artery; ACE, external carotid artery, ACI, internal carotid artery. (E) Role of platelet adhesion for atherosclerotic lesion formation in the aortic sinus (top panel) and the right and left main coronary arteries (bottom panel, plaque area is presented as percentage of total cross-sectional intimal area). 18-wk-old ApoE−/− mice were treated with vehicle (Control), irrelevant rat IgG, or anti-GPIbα mAb for 12 wk. Atherosclerotic lesion formation was assessed in the aortic sinus and the proximal coronary arteries. Inhibition of platelet adhesion induced a significant reduction in atherosclerotic lesion formation in the aortic sinus and the proximal coronary arteries. Aortic plaque area is presented in μm2; coronary plaque area is given as percentage of the area delimited by the internal elastic lamina (intimal area). Mean ± SEM, P < 0.05 versus Control. Representative histological sections of the aortic sinus and the coronary arteries stained with elastica van Giesson reagent are presented in F and G, respectively (original magnification: 200-fold).
Mentions: Strikingly, inhibition of platelet adhesion (for 12 wk) significantly reduced the increase in vascular resistance index in 18-wk-old ApoE−/− mice, when compared with untreated 18-wk-old animals (Fig. 4 A, P < 0.05). Furthermore, the anti-GPIbα treatment dramatically limited atherosclerotic lesion formation as compared with control animals. Quantitative computer-assisted image analysis showed an ∼90% reduction in the extent of fatty streak formation in 18-wk-old ApoE−/− mice treated with anti-GPIbα mAb for 12 wk, as assessed by Sudan III staining (Fig. 4 B). Moreover, anti–GPIbα-treated ApoE−/− mice showed substantial decreases in cross-sectional carotid plaque area (by 81%, P < 0.05) (Fig. 4 C). In contrast, in ApoE−/− mice, treated with isotype-matched control rat IgG, atheroprogression in the carotid artery was neither accelerated nor retarded, when compared with untreated ApoE−/− mice.

Bottom Line: Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE(-)(/)(-) mice before the development of manifest atherosclerotic lesions.Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes.Prolonged blockade of platelet adhesion in ApoE(-)(/)(-) mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries.

View Article: PubMed Central - PubMed

Affiliation: Deutsches Herzzentrum und 1. Medizinische Klinik, Technische Universität München, Germany. massberg@dhm.mhn.de

ABSTRACT
The contribution of platelets to the process of atherosclerosis remains unclear. Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE(-)(/)(-) mice before the development of manifest atherosclerotic lesions. Platelet-endothelial cell interaction involved both platelet glycoprotein (GP)Ibalpha and GPIIb-IIIa. Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes. Prolonged blockade of platelet adhesion in ApoE(-)(/)(-) mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries. These findings establish the platelet as a major player in initiation of the atherogenetic process.

Show MeSH
Related in: MedlinePlus