The evolving science of atherothrombotic disease
Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls Universität Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany
* Corresponding author. Tel: +49 7071 298 3688; fax: +49 89 1218 4053, E-mail address: meinrad.gawaz{at}med.uni.tuebingen.de
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Abstract |
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 Top Abstract IntroductionMechanisms of platelet...Atherogenesis and...Platelet-endothelial progenitor...SummaryFundingReferences |
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Atherosclerosis is a systemic inflammatory disease characterized by the accumulation of inflammatory cells in the intima of large arteries. The presence of platelets at the site of inflammation and endothelial injury has been known since the early 1960s. In the following years, it was generally accepted that rupture or erosion of advanced atherosclerotic lesions initiates platelet activation and aggregation on the thrombogenic surface of a disrupted atherosclerotic plaque. Thrombotic vascular occlusion is associated with ischaemic episodes in the retina, brain, heart, and other organs. While it is widely accepted that platelets play a significant role in thromboembolic events generated by atherosclerotic lesions (atherothrombosis), their involvement in the initiation of the atherosclerotic process has not been widely recognized by the scientific community. An expanding body of evidence on the role of platelets in the development of atherosclerotic lesions continues to build. Platelets bind to leukocytes and endothelial cells, and initiate the transformation of monocytes into macrophages. Additionally, platelets internalize oxidized phospholipids and promote foam cell formation, as well as recruit progenitor cells that are able to differentiate into foam or endothelial cells. In total, platelets play a key role in the initiation, development, and total extent of atherosclerotic lesions.
Key Words: Atherosclerosis • Platelets • Endothelial progenitor cells • Thrombosis
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Introduction |
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TopAbstractIntroductionMechanisms of platelet...Atherogenesis and...Platelet-endothelial progenitor...SummaryFundingReferences |
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Platelets are the main trigger of arterial thrombosis. They circulate down the vascular branch without interacting with structures of the vessel wall. However, at the site of vascular lesions, they are recruited towards the vessel injury, and they adhere, become activated, and form microaggregates (Figure 1).1 Through their interaction with the coagulation cascade, activated platelets form a solid thrombus leading to unstable angina or myocardial infarction (MI) [acute coronary syndromes (ACS)].
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In this review, we will focus on the basic science of platelets and their role in atherothrombotic disease.
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Mechanisms of platelet activation |
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When the endothelial monolayer is disrupted, subendothelial structures are presented towards the bloodstream. The main components of the subendothelium are extracellular matrix proteins, including collagen. Platelets express a set of adhesion receptors on their surface, including the von Willebrand factor receptor glycoprotein Ib (GP Ib) and the collagen receptor glycoprotein VI (GP VI). Platelets adhere to the von Willebrand factor and collagen immobilized within the extracellular matrix of the subendothelium mainly by way of GP Ib and GP VI as they start to change their morphology. They spread on top of these lesions and cover up the vascular injury. Thereafter, they become activated and start to degranulate proaggregation substances, such as adenosine diphosphate, which, in turn, further activates the platelets propagating thrombus formation. This process can be inhibited by antiplatelet compounds, including the thienopyridines ticlopidine, clopidogrel, and prasugrel.
The formation of coronary platelet activation is often clinically silent and does not necessarily induce ACS. However, even a small not occluding thrombus can lead to reduced myocardial perfusion, resulting in angina pectoris and myocardial damage. If this process is not controlled, total occlusion of the vessel will occur, leading to a full MI.
It is clearly indicated that platelets trigger acute coronary thrombosis, leading to acute MI. However, platelets often adhere to vascular lesions without forming a clinically significant intracoronary thrombus (asymptomatic coronary thrombosis). Thereafter, platelet aggregates stimulate vascular reactions resulting either in vascular healing or in disease progression (vascular remodelling). Often we do not recognize this coronary thrombosis because it is asymptomatic, but it may be occurring constantly in high-risk patients and may have a major impact on disease progression.
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Atherogenesis and atheroprogression |
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TopAbstractIntroductionMechanisms of platelet...Atherogenesis and...Platelet-endothelial progenitor...SummaryFundingReferences |
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What is the consequence of asymptomatic coronary thrombosis or arterial platelet adhesion to vascular lesions, and what is the role of platelets in the course of the disease? Atherogenesis is a long-lasting disease that starts very early. We already recognize fatty streaks and intimal proliferation in early life. With time, these lesions become consolidated and calcified, forming atheromas. At one stage of the disease, these atheromas tend to rupture or develop into an endothelial lesion leading to coronary thrombosis and MI. On the other hand, platelet accumulation at the site of coronary lesions may induce chronic inflammation and support atheroprogression, as has been seen in animal models. In this process, atherosclerosis is a platelet-driven chronic inflammatory disease.
When we look at recent reviews on the role of platelets in regulating atherosclerosis and inflammation (Figure 2),2,3 we see that platelets are in the centre to interact with monocytes, other blood-borne cells, other endothelial cells, and endothelial progenitor cells. Platelets regulate all processes of chronic and acute inflammation through interaction with these cells.
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B, nuclear factor-kappa B; PAI-1, plasminogen activator inhibitor-1; PMN, neutrophils; TNF-What is known about platelet–endothelial interaction in terms of atherogenesis? From a study we conducted,4,5 we know that platelets adhere to the endothelial monolayer, especially in patients with acute MI. This adhesion can be reduced by GP IIb–IIIa receptor blockers. When we looked into the microcirculation, we realized there is massive platelet blocking and aggregation going on, leading to disturbances of the microcirculation and further myocardial damage. Areas of massive platelet aggregation and adhesion to the endothelial wall are indicative of a very fast trigger moment of platelet/endothelial interaction, leading to diseased arteries.
What is the consequence of enhanced platelet endothelial adhesion? When platelets come into contact with the endothelium they start to release their granules, leading to endothelial inflammation. There are a number of proinflammatory substances within the granules (e.g. platelet-derived growth factor, CD40L) that are released into the microenvironment. In addition, the platelets start to generate new substances, including tissue factor and interleukin-1, which are generated from the messenger ribonucleic acid of platelets since platelets do not have a nucleus.
So what are the consequences for the disease progress? We conducted a study using apolipoprotein E (apoE) mice that spontaneously develop atherosclerotic lesions.6 When we looked by intramicroscopy, there was no substantial platelet adhesion in the area of carotid bifurcation in wild-type mice. However, when we looked at apoE-deficient mice that developed spontaneous atherosclerosis, we could see, in the very early stage, platelet adhesion in this carotid bifurcation where we did not see morphologic plaques. While this progress is occurring and we can already see plaque formation, we can also see massive platelet adhesion. Leukocyte accumulation follows platelet adhesion. This means that platelet adhesion to the endothelium or vascular wall occurs at a very early phase of atherosclerosis and stimulates further inflammatory reactions, such as leukocyte recruitment.
When leukocyte accumulation was calculated, we saw in the very early weeks that platelet adhesion was enhanced substantially during arterial progression. The main point is that platelet adhesion comes first, preceding leukocyte adhesion. Weeks before leukocyte adhesion occurs, platelets are already present, indicating that platelets are the major triggers of atherosclerosis.
What would happen if we inhibited platelet adhesion to the vessel wall? Mice were administered a chronic adhesion blocker, an antibody that recognizes the very central adhesion receptor. A substantial reduction in atherosclerotic lesion formation was seen when these mice were compared with control mice. This is evidence that platelet adhesion to the vascular wall triggers and accelerates atherosclerosis.
When atherosclerosis platelets attach to the endothelial cell, they modify the endothelial cells to become pro-adhesive, and pro-chemotactic. Then the leukocytes are attracted, transmigrate, and form the foam cells and plaques. This is how platelets may be involved in platelet-endothelium adhesion (Figure 3).2
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Platelet–endothelial progenitor cell adhesion |
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We know from clinical studies that patients who have manifest coronary artery disease are at high risk for cardiovascular death. These patients, who also have a lower number of circulating endothelial progenitor cells (EPCs), have a poorer prognosis than do patients with a higher number of circulating EPCs. This indicates that circulating EPCs somehow modulate or regenerate or are involved in coronary artery disease. One theory suggests that there is a constant on/off of dying endothelial cells in high-risk patients. So, there is a requirement that these vascular lesions have to be consolidated and repaired. During these repairs, platelets and new EPCs are primarily involved to form a new endothelium that repairs these constantly occurring vascular adhesions in high-risk patients.
The question that arises is how do EPCs recognize the vascular lesions? How do they hone in on peripheral organs or vascular arteries? One major factor for the honing of stem cells or EPCs is the chemotaxin stromal cell-derived factor-1 (SDF-1). I want to briefly summarize a few aspects of what we found over the past few years with respect to the consequences of the action of platelet and endothelial progenitor cells. When EPCs start to hone, they have to be attracted and migrate to the top of the vascular lesions. We found that platelets are the first to recognize vascular lesions. The role of platelets is to recognize vascular lesions, cover them, and heal them. We found that platelets have substantial amounts of SDF-1 in their granules, and they release them once they adhere to the extracellular matrix.7,8
When we looked at the consequence of adhering platelets for the chemotaxis of EPCs, we found that platelets are a trigger of chemotaxis and EPC migration. We also found that platelets modify the undirected migration of EPCs. What is interesting is that in acute MI, where we know that platelets are activated, they present SDF-1 on their activated surface compared with what is seen in patients with coronary artery disease. We also know that the number of circulating progenitor cells is enhanced in the setting of ACS. We now realize that the SDF-1 on the platelets correlates nicely with the number of circulating EPCs in patients with MI. This suggests that platelets are the driving force behind the honing of liberation of progenitor cells from the bone marrow to the peripheral organs where activated platelets are present.9
We also know that platelets interact directly with EPCs similar to monocytes, and that EPCs adhere to immobilized platelets (Figure 2). We conducted an experiment in a flow chamber where platelets were immobilized and EPCs were perfused over the immobilized platelets.9
Some of the EPCs are constantly adhering, some are rolling, and when you immobilize platelets in the presence of chemotaxic factor SDF-1, there is a substantial reduction in adhesion. This is seen not only in flow chambers, but in the microcirculation of ischaemic tissue. When these experiments are performed under inhibition of SDF-1, there is virtually no adherent EPCs. This means that platelets that are plucking the microcirculation are also responsible for the adhesion and recruitment of EPCs, and potentially for repairing these areas.
What happens when the platelets recognize EPCs and when EPCs start to adhere to platelets? In culture experiments, we see that EPCs form the so-called endothelial colonies; they change their differentiation towards endothelial cells, and this is also regulated by SDF-1. But when we modify the culture conditions, we see monocytes, as well as endothelial cells, formed in the presence of platelets. We performed an experiment over several hours on the co-cultures and saw that the EPCs start to digest the reddish dyed platelets.10
The platelets become larger and more red, and you realize that the platelet cord is digested. So, there is a significant uptake of EPCs by platelets, leading to monocytes, macrophages and, in the end, foam cells.
Thus, our hypothesis is that platelets are the major trigger for vascular lesions, and they recruit EPCs towards these lesions. Depending on the conditions present in this microenvironment, EPCs may start on top of platelets to become endothelial cells or may start to become monocyte macrophages. This may well be the bottleneck where the vascular lesions either go in the direction of vascular healing or into disease progression.
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Summary |
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TopAbstractIntroductionMechanisms of platelet...Atherogenesis and...Platelet-endothelial progenitor...SummaryFundingReferences |
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Platelets are very active cells, although they do not have nuclei. They are very active in migrating, and we are just beginning to understand platelet physiology and pathophysiology of platelet aggregation and thrombus formation.
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Funding |
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TopAbstractIntroductionMechanisms of platelet...Atherogenesis and...Platelet-endothelial progenitor...SummaryFundingReferences |
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The author is grateful for continuous funding of his research through the Deutsche Forschungsgemeinschaft (Transregio-SFB 19) and the Bundesministerium für Bildung und Forschung. Financial support provided by Daiichi Sankyo, Inc and Eli Lilly and Company.
Conflict of interest: none declared.
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References |
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TopAbstractIntroductionMechanisms of platelet...Atherogenesis and...Platelet-endothelial progenitor...SummaryFundingReferences |
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