Sub Programs
IIIA Vascular development
The concept has emerged that major cardiovascular diseases have their origin in abnormal development of the vascular system. Originally, such abnormalities were mostly held responsible for a number of rather rare congenital neonatal diseases. There is, however, an increasing awareness that major diseases in adults are based upon mechanisms of abnormal vascular growth, with - in some cases - origins in early life. Abnormalities in vascular growth are now regarded important events in tumor growth, coronary artery disease, diabetes, hypertension and peripheral ischemic disease. This interest has even led to a considerable pharmaceutical activity in the area of therapeutic angiogenesis and antiangiogenesis. The factors and mechanisms which regulate embryonic vessel development are presently the subject of intensive research. The continued generation of knock-out animals and development of new transgenic techniques has greatly enhanced knowledge on molecular mechanisms of early vascular growth. However, much less is known on mechanisms governing the formation of mature vascular trees. It now appears that a tightly regulated genetic program directs the patterning of nascent endothelial tubes, including the initial determination of arterial and venous endothelial networks. This primary vascular network is basically established in the absence of flow and pressure. The subsequent formation of a vascular network depends on hemodynamic factors. Whereas much is known on the role of hemodynamic factors in vessel wall remodeling (see subtheme b), the relationship between hemodynamics and vascular network architecture is still largely unexplored. Similarly, it is still unknown whether the same mechanisms that determine embryonic vessel formation contribute to vascular adaptations in later life. A working hypothesis is that repertoires of embryonic vascular development are activated in later life when tissues are exposed to challenges, such as hypox ia/ischemia or mechanical stresses. According to this view, cardiovascular pathologies arise upon an inappropriate response of these re-activated mechanisms.
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IIIB Vascular model and remodelling
Major cardiovascular diseases such as hypertension, diabetes and atherosclerosis have a strong structural component. These structural alterations have detrimental hemodynamic consequences through their effects on the mechanical properties of the vessel wall. For instance, resistance artery remodeling contributes to elevated peripheral resistance in essential hypertension, conduit artery fibrosis contributes to systolic hypertension in the elderly, and inadequate expansion of the intact media beneath an arterial lesion contributes to the formation of a flow limiting stenosis.
That vascular structural changes adversely affect hemodynamics is in sharp contrast to the remarkable capacity of especially muscular arteries of healthy young individuals to adjust their lumen diameter and wall mass in response to acute and chronic changes in blood flow and blood pressure. This adaptive and compensatory remodeling operates during the entire development and maturation of the vascular system, and can be observed in selected situations in the adult such as the female reproductive system and the establishment of collateral circulations. It has been proposed that the endothelium is the main shearsensor and that the cytoskeleton plays in general a key role in biological responses to mechanical factors.
Manipulation of vascular remodeling with the aim to improve cardiovascular function in cardiovascular diseases, requires detailed knowledge of the (ultra)structural basis of vessel wall mechanics, of the transition from acute vasomotor to chronic vascular structural responses, and of the signaling and paracrine mechanisms that can modulate the preexisting structure. Comparative studies of large conduit arteries, small muscular arteries and arterioles and attention for the endothelium, may be helpful in this respect. top
That vascular structural changes adversely affect hemodynamics is in sharp contrast to the remarkable capacity of especially muscular arteries of healthy young individuals to adjust their lumen diameter and wall mass in response to acute and chronic changes in blood flow and blood pressure. This adaptive and compensatory remodeling operates during the entire development and maturation of the vascular system, and can be observed in selected situations in the adult such as the female reproductive system and the establishment of collateral circulations. It has been proposed that the endothelium is the main shearsensor and that the cytoskeleton plays in general a key role in biological responses to mechanical factors.
Manipulation of vascular remodeling with the aim to improve cardiovascular function in cardiovascular diseases, requires detailed knowledge of the (ultra)structural basis of vessel wall mechanics, of the transition from acute vasomotor to chronic vascular structural responses, and of the signaling and paracrine mechanisms that can modulate the preexisting structure. Comparative studies of large conduit arteries, small muscular arteries and arterioles and attention for the endothelium, may be helpful in this respect. top
IIIC Predisposition to vascular disease
Over the past five years it has been increasingly recognized that patients with cardiovascular disease may display heterogeneity with respect to genetic factors. In the case of hypertension and related disorders investigations into the genetic predisposition to disease or complications have focused largely on the components of the renin-angiotensin system. Clinically, the main targets of research involve the production of angiotensin II, e.g. by angiotensin-converting en zy me (ACE), and its action through specific receptors, of which the AT1 receptor is the most relevant one. The gene that regulates the production of ACE is now known to display an im portant deletion/insertion polymorphism that is associated with a variety of cardiovascular complications. Familial Combined Hyperlipidemia (FCH) is a genetic disorder with a high frequency in the population (1:100 in dividuals), representing the most common genetic hyperlipidemia in man. It is associated with an ap proximately 10-fold higher risk on premature myocardial infarction and coronary artery disease. Lipoprotein hypersecretion by the liver, in combination with impaired elimination of hepatic very-low-density lipoproteins and intestinal chylo microns, result in increased plasma concentrations of the structural apoprotein, apolipoprotein B, and its isoforms apoB48 and apoB100. Increased lipid supply, in the form of elevated plasma fatty acid concentrations, is considered the metabolic factor that drives the hypersecretion of lipoproteins from liver. Type 2 diabetes mellitus is characterized by abnormal glucose homeostasis, but also by elevated plasma fatty acid concentrations and often hyperlipidemia with elevated plasma apo B. One of the hypotheses is that the increased fatty acid plasma concentrations in FCH and type 2 diabetes mellitus are caused by insufficient suppression of adipose tissue lipolysis, secundary to insulin resistance, or reduced adipose tissue fatty acid uptake, or a combination of both.
A third program focusses on the interactions between the metabolic derangements and possible environmental and genetic influences in the predisposition to vascular abnormalities in diabetes mellitus and insulin resistance. The program focusses on clinical and biochemical abnormalities involved in the etiology and pathogenesis of micro- and macro-vascular and neurologic complications, which are associated with (aquired) metabolic diseases. Special attention is paid to the effects induced by and associated with hyperglycemia in diabetes mellitus, other relevant disturbances of carbohydrate and lipid metabolism, the relevance of fatty acids and lipoprotein changes, and disturbances of coagulation and fibrinolysis in these disease states. Furthermore, the cross-talk between metabolism and the vessel wall is studied as disturbances in this interaction could be fundamental in the development of both insulin resistance and vascular disease. We will assess in addition which environmental and genetic variations are of influence for these processes, and also investigate by which (pharmacologic) interventions these pathophysiologic processes and their sequeale may be beneficially in fluenced. Several tools are used, varying from relevant animal models and cell culture systems to intervention studies in humans. Results of the studies in the animal research program will be applied in the human studies and vice versa. top
A third program focusses on the interactions between the metabolic derangements and possible environmental and genetic influences in the predisposition to vascular abnormalities in diabetes mellitus and insulin resistance. The program focusses on clinical and biochemical abnormalities involved in the etiology and pathogenesis of micro- and macro-vascular and neurologic complications, which are associated with (aquired) metabolic diseases. Special attention is paid to the effects induced by and associated with hyperglycemia in diabetes mellitus, other relevant disturbances of carbohydrate and lipid metabolism, the relevance of fatty acids and lipoprotein changes, and disturbances of coagulation and fibrinolysis in these disease states. Furthermore, the cross-talk between metabolism and the vessel wall is studied as disturbances in this interaction could be fundamental in the development of both insulin resistance and vascular disease. We will assess in addition which environmental and genetic variations are of influence for these processes, and also investigate by which (pharmacologic) interventions these pathophysiologic processes and their sequeale may be beneficially in fluenced. Several tools are used, varying from relevant animal models and cell culture systems to intervention studies in humans. Results of the studies in the animal research program will be applied in the human studies and vice versa. top
IIID Mechanism of vascular occlusion
This subtheme focuses on experimental research into the causes and consequences of vascular occlusion, with special emphasis on atherosclerosis. The main objective is to elucidate the key factors that control the onset and progression of atherosclerosis, as well as the its ultimate consequence, vascular occlusion. Since atherosclerosis is currently thought to be a chronic in flammatory disease, with the endothelium as the intermediate between blood and vessel wall, we focus our research on the role of lipoproteins, macrophages, other blood-vesselwall interactions and the effects of infectious agents on the vesselwall. Furthermore mouse and human atherosclerotic plaques will be used to identify and validate new targets for therapeutic interventions.
The onset of atherogenesis is characterized by the activation of endothelial cells, followed by monocyte attraction, and differentiation into macro phages within the intima. This process is stimulated in the presence of increased lipoprotein levels. These lipo proteins become trapped within the intimal space. Subsequently, lipoproteins are being modified by a range of inflammatory mediators produced by endothelial cells and macrophages. Modified lipoproteins are being taken up by macrophages and endothelial cells via scavenger receptors, and lead to the activation of the transcription factor NF-kB. Activated NF-kB is crucial for the expression of inflammatory genes, such as cytokines and adhesion molecules, facilitating further recruitment and proliferation of macrophages within the atherosclerotic lesion. The activated macro phages cause a progressive inflammatory reaction, which ultimately leads to the accumulation of foam cells followed by the development of an advanced atherosclerotic plaque in volving activated T-cells The aim of the research is to delineate the role of lipoproteins, macro phages and inflammation during athe rogenesis by in vivo studies in transgenic mice. These events leads to a more pronounced vascular injury characterized by vascular injury, blood platelets adhering to the subendothelium, be coming activated, aggregating and for ming a thrombus. In this process, factors like von Willebrand factor, fibrinogen and thrombin in combination with their specific receptors play an important role. A vascular occlusion not only results in a decrease in tissue perfusion, but also induces interactions between endothelium and leukocytes and/or platelets; due to release of oxygen radicals and proteolytic enzymes these cells may contribute to tissue damage. At present the involvement of adhesion molecules and endothelial cells is studied extensively. The exact reaction pattern of endothelial cells in such diseases appears to be very dependent on their specific site in the vascular system. It is becoming clear that endothelial cells display remarkable heterogeneity in different organs, and even between different vessel types in the same organ. The microenvironment of the endothelium, consisting of surrounding cells and matrix constituents as well as the flowing blood, contributes to this high level of heterogeneity, and even adult endothelium can reversibly change its functions due to changes in its environment. There is growing evidence that infections with Chlamydia pneumoniae and cytomegalovirus are associated with vascular disease. These microorganisms are known to induce persistent infection in macrophages and smooth muscle cells and by this way could participate in chronic inflammatory responses in the vascular wall. The association of infections with cardiovascular disease has been demonstrated in numerous seroepidmiological studies.
Although the mechanism is not clear several data indicate that infection of cells in the vessel wall i.e. endothelial cells, smooth muscle cells and macrophages are important in the process (direct effect). Infection of endo thelium leads to activation of these cells resulting in the production of cytokines and chemotactic factors and in the upregulation of adhesion molecules. Infection of smooth muscle cells can lead to increased proliferation and migration of these cells and by this way it is an important factor in the formation of a neointima.
Another mechanism that will be explored is whether systemic (inflammatory) reactions induced by (multiple) infections result in an enhancement of the atherosclerotic process (indirect effect).
At this point in time we are not able to stratify atherosclerotic plaques in instabile, thrombogenic plaques or in stable, non-thrombogenic plaques. Plaque characterisation is only based on morphologic criteria like the presence of a lipid core, a thin fibreus cap, cap erosion and the presence of an inflammatory infiltrate. Potential markers of plaque instability are FVII-TF, PAI-1, fibrin, fibrinogen and several adhesion molecules. The problem is that they can only be used after the plaque tissue has been removed, but have no value in predicting plaque instability or in the in vivo diagnosis of an instabile plaque. Even modern imaging techniques, like B-mode ultrasound imaging and magnetic resonance angiography (MRA), are not able to dissociate stable from instabile plaques. It would therefore be of great help to have markers of plaque instability that can be used for non-invasive imaging or therapy. The objective of one of programs in this subtheme is to develop new markers between stable and instable plaques by identifying differentially expressed genes from both 2 plaque types. top
The onset of atherogenesis is characterized by the activation of endothelial cells, followed by monocyte attraction, and differentiation into macro phages within the intima. This process is stimulated in the presence of increased lipoprotein levels. These lipo proteins become trapped within the intimal space. Subsequently, lipoproteins are being modified by a range of inflammatory mediators produced by endothelial cells and macrophages. Modified lipoproteins are being taken up by macrophages and endothelial cells via scavenger receptors, and lead to the activation of the transcription factor NF-kB. Activated NF-kB is crucial for the expression of inflammatory genes, such as cytokines and adhesion molecules, facilitating further recruitment and proliferation of macrophages within the atherosclerotic lesion. The activated macro phages cause a progressive inflammatory reaction, which ultimately leads to the accumulation of foam cells followed by the development of an advanced atherosclerotic plaque in volving activated T-cells The aim of the research is to delineate the role of lipoproteins, macro phages and inflammation during athe rogenesis by in vivo studies in transgenic mice. These events leads to a more pronounced vascular injury characterized by vascular injury, blood platelets adhering to the subendothelium, be coming activated, aggregating and for ming a thrombus. In this process, factors like von Willebrand factor, fibrinogen and thrombin in combination with their specific receptors play an important role. A vascular occlusion not only results in a decrease in tissue perfusion, but also induces interactions between endothelium and leukocytes and/or platelets; due to release of oxygen radicals and proteolytic enzymes these cells may contribute to tissue damage. At present the involvement of adhesion molecules and endothelial cells is studied extensively. The exact reaction pattern of endothelial cells in such diseases appears to be very dependent on their specific site in the vascular system. It is becoming clear that endothelial cells display remarkable heterogeneity in different organs, and even between different vessel types in the same organ. The microenvironment of the endothelium, consisting of surrounding cells and matrix constituents as well as the flowing blood, contributes to this high level of heterogeneity, and even adult endothelium can reversibly change its functions due to changes in its environment. There is growing evidence that infections with Chlamydia pneumoniae and cytomegalovirus are associated with vascular disease. These microorganisms are known to induce persistent infection in macrophages and smooth muscle cells and by this way could participate in chronic inflammatory responses in the vascular wall. The association of infections with cardiovascular disease has been demonstrated in numerous seroepidmiological studies.
Although the mechanism is not clear several data indicate that infection of cells in the vessel wall i.e. endothelial cells, smooth muscle cells and macrophages are important in the process (direct effect). Infection of endo thelium leads to activation of these cells resulting in the production of cytokines and chemotactic factors and in the upregulation of adhesion molecules. Infection of smooth muscle cells can lead to increased proliferation and migration of these cells and by this way it is an important factor in the formation of a neointima.
Another mechanism that will be explored is whether systemic (inflammatory) reactions induced by (multiple) infections result in an enhancement of the atherosclerotic process (indirect effect).
At this point in time we are not able to stratify atherosclerotic plaques in instabile, thrombogenic plaques or in stable, non-thrombogenic plaques. Plaque characterisation is only based on morphologic criteria like the presence of a lipid core, a thin fibreus cap, cap erosion and the presence of an inflammatory infiltrate. Potential markers of plaque instability are FVII-TF, PAI-1, fibrin, fibrinogen and several adhesion molecules. The problem is that they can only be used after the plaque tissue has been removed, but have no value in predicting plaque instability or in the in vivo diagnosis of an instabile plaque. Even modern imaging techniques, like B-mode ultrasound imaging and magnetic resonance angiography (MRA), are not able to dissociate stable from instabile plaques. It would therefore be of great help to have markers of plaque instability that can be used for non-invasive imaging or therapy. The objective of one of programs in this subtheme is to develop new markers between stable and instable plaques by identifying differentially expressed genes from both 2 plaque types. top
IIIE Vascular medicine
Vascular medicine is a rapidly evolving new medical discipline. It is the clinical counterpart of the research field known as vascular biology. Vascular medicine has developed primarily for 2 reasons. First, it provides the frame work for integration of input from the many clinical disciplines that collaborate in the care for patients with vascular disease. Second, it is the frame work for evaluating the theories about mechanisms of disease and the potential treatment strategies that arise from research in the field of vascular biology. The increasing and worldwide awareness of this need for a multidisciplinary approach towards cardiovascular patients, who mostly have multiple manifestations of the underlying systemic disease, has already resulted in a great variety of inventorial clinical and epidemiological studies showing the coexistence of multiple manifestations of vascular diseases or risk factors in patient categories which were primarily discipline determined.
The new Theme IIIE brings to gether the medical specialists dealing with cardiovascular patients. The purpose of this is the improvement of evaluation and application of new cardiovascular diagnostic and therapeutic technologies and strategies in a clinical setting and stimulation of joint fundamental research on vascular diseases in cooperation with basic scientists in the field of vascular biology.
One of the research programs in this subtheme focusses on the clinical evaluation of gene transfer techniques since significant progress has been made toward gene transfer as an approach to the unresolved problem of restenosis and chronic vascular occlusion. Several potentially therapeutic gene products have been identified (VEGF, b-FGF, HGF, e-NOS). However, several challenges have evolved from preceding experiments: (1) the need for clinically practical methods of delivery, (2) issues of host immune response to the most efficient adenoviral vectors, (3) comparatively low efficiency typical of less immunogenic vectors and (4) validation of the biological efficacy of gene products in the context of pre-existent arterial disease. Clinically reasonable delivery systems with the potential for efficient delivery are currently being evaluated. Increases in delivery efficiency may be achieved by incorporating vectors into a variety of matrices, as well as the use of extraluminal/ intramural delivery sites where the vectors will not be washed out by the blood stream. The advent of efficient viral vectors containing minimal genetic material of viral origin, such as advanced-generation adenoviruses and adeno-associated viruses, should help to overcome the vector based issues of host-immune or inflammatory responses. Finally, the availability of genetically engineered animal (mouse) models of atherosclerosis will increase our understanding of the pathobiology of restenosis and will help us validate the biological efficacy of gene products in the context of pre-existent arterial disease.
A last program focusses on imaging of vascular disease. Gadolinium contrast-enhanced MR angiography (MRA) provides detailed 3D information about vascular anatomy. Arterial diseases like aneurysms, stenoses and obstructions in the brain, kidneys and lower extremities, can be diagnosed accurately and non-invasively within minutes. This method has the potential to replace x-ray angiography in many anatomic areas. However, MRA of the coronary arteries is not yet ready for clinical application. Faster imaging techniques need to be developed to overcome problems of respiratory and cardiac motion while providing sufficiently high spatial resolution with a good signal-to-noise ratio. The application of new MR contrast media (so called blood pool agents) may be very advantageous in coronary MRA. Additionally, MR imaging can delineate areas of altered blood flow in myocardial infarction and in very early stages of human stroke.
Imaging techniques can also provide information about the extent and progression of atherosclerosis. Ultra sound and MR imaging both have sufficient resolution and contrast to de monstrate arterial layers and to identify atheroma. Ultrasound has the advantage of speed and resolution, whereas MR imaging has superior contrast in the depiction of atheroma. However, the use of intravascular probes or coils often remains necessary to obtain sufficient image quality. Computer tomography (CT) can be very useful to detect and quantify vessel wall calcifications and CT quantification of coronary artery calcifications has proven to be a reliable predictor of coronary artery disease. As the prevalence of atherosclerosis increases worldwide, there is a pressing need for investigators to re fine and evaluate this and other noninvasive techniques, in order to ensure reliable identification of individuals at increased risk for the development of complications during the long pre symptomatic phase of the disease.
The program on molecular and cellular aspects of vascular growth has close links to the research lines IIIa, IIIc and IIIe. It deals with certain aspects of the role of growth factors in vascular growth including angiogenesis, arteriogenesis and atherogenesis. Peptide growth factors such as platelet- derived growth factor and vascular endothelial growth factor are central mediators for structural and functional changes within the vessel wall. All these growth factors act by stimulating receptor tyrosine kinases to induce and trigger certain signalling cascades that lead to cellular proliferation, migration, matrix formation and the modification of the cellular gene expression profiles. Peptide growth factors either act in an autocrine or paracrine fashion, the latter can be direct, i.e. via diffusion, or indirect via release from circulating cells (monocytes, macrophages, endothelial progenitor cells, stem cells). The different projects of the vascular growth program deal with functional and mechanistic aspects namely the role of growth factors in angiogenesis, arteriogenesis and atherogenesis; the mechanisms of action including signal transduction studies, as well as with the identification and characterization of potential signal transduction defects. These could well represent a basis for understanding defective vascular regeneration. The different projects of Dr. Waltenberger that have been transferred into the Maastricht program at Carim deal with the negative impact of cardiovascular risk factors on the dysfunction of endothelial cells and monocytes, the cellular and molecular consequences of a cytomegaly virus infection in the coronary artery, circulating endothelial precursor cells and vascular repair, the role of VEGF in arteriogenesis, and the role of VEGF and VEGF substitutes and gene therapies to maintain the integrity of the arterial wall. Finally the group is holding a grant on the pharmacogenic and antisense delivery for therapy of restenosis. top
The new Theme IIIE brings to gether the medical specialists dealing with cardiovascular patients. The purpose of this is the improvement of evaluation and application of new cardiovascular diagnostic and therapeutic technologies and strategies in a clinical setting and stimulation of joint fundamental research on vascular diseases in cooperation with basic scientists in the field of vascular biology.
One of the research programs in this subtheme focusses on the clinical evaluation of gene transfer techniques since significant progress has been made toward gene transfer as an approach to the unresolved problem of restenosis and chronic vascular occlusion. Several potentially therapeutic gene products have been identified (VEGF, b-FGF, HGF, e-NOS). However, several challenges have evolved from preceding experiments: (1) the need for clinically practical methods of delivery, (2) issues of host immune response to the most efficient adenoviral vectors, (3) comparatively low efficiency typical of less immunogenic vectors and (4) validation of the biological efficacy of gene products in the context of pre-existent arterial disease. Clinically reasonable delivery systems with the potential for efficient delivery are currently being evaluated. Increases in delivery efficiency may be achieved by incorporating vectors into a variety of matrices, as well as the use of extraluminal/ intramural delivery sites where the vectors will not be washed out by the blood stream. The advent of efficient viral vectors containing minimal genetic material of viral origin, such as advanced-generation adenoviruses and adeno-associated viruses, should help to overcome the vector based issues of host-immune or inflammatory responses. Finally, the availability of genetically engineered animal (mouse) models of atherosclerosis will increase our understanding of the pathobiology of restenosis and will help us validate the biological efficacy of gene products in the context of pre-existent arterial disease.
A last program focusses on imaging of vascular disease. Gadolinium contrast-enhanced MR angiography (MRA) provides detailed 3D information about vascular anatomy. Arterial diseases like aneurysms, stenoses and obstructions in the brain, kidneys and lower extremities, can be diagnosed accurately and non-invasively within minutes. This method has the potential to replace x-ray angiography in many anatomic areas. However, MRA of the coronary arteries is not yet ready for clinical application. Faster imaging techniques need to be developed to overcome problems of respiratory and cardiac motion while providing sufficiently high spatial resolution with a good signal-to-noise ratio. The application of new MR contrast media (so called blood pool agents) may be very advantageous in coronary MRA. Additionally, MR imaging can delineate areas of altered blood flow in myocardial infarction and in very early stages of human stroke.
Imaging techniques can also provide information about the extent and progression of atherosclerosis. Ultra sound and MR imaging both have sufficient resolution and contrast to de monstrate arterial layers and to identify atheroma. Ultrasound has the advantage of speed and resolution, whereas MR imaging has superior contrast in the depiction of atheroma. However, the use of intravascular probes or coils often remains necessary to obtain sufficient image quality. Computer tomography (CT) can be very useful to detect and quantify vessel wall calcifications and CT quantification of coronary artery calcifications has proven to be a reliable predictor of coronary artery disease. As the prevalence of atherosclerosis increases worldwide, there is a pressing need for investigators to re fine and evaluate this and other noninvasive techniques, in order to ensure reliable identification of individuals at increased risk for the development of complications during the long pre symptomatic phase of the disease.
The program on molecular and cellular aspects of vascular growth has close links to the research lines IIIa, IIIc and IIIe. It deals with certain aspects of the role of growth factors in vascular growth including angiogenesis, arteriogenesis and atherogenesis. Peptide growth factors such as platelet- derived growth factor and vascular endothelial growth factor are central mediators for structural and functional changes within the vessel wall. All these growth factors act by stimulating receptor tyrosine kinases to induce and trigger certain signalling cascades that lead to cellular proliferation, migration, matrix formation and the modification of the cellular gene expression profiles. Peptide growth factors either act in an autocrine or paracrine fashion, the latter can be direct, i.e. via diffusion, or indirect via release from circulating cells (monocytes, macrophages, endothelial progenitor cells, stem cells). The different projects of the vascular growth program deal with functional and mechanistic aspects namely the role of growth factors in angiogenesis, arteriogenesis and atherogenesis; the mechanisms of action including signal transduction studies, as well as with the identification and characterization of potential signal transduction defects. These could well represent a basis for understanding defective vascular regeneration. The different projects of Dr. Waltenberger that have been transferred into the Maastricht program at Carim deal with the negative impact of cardiovascular risk factors on the dysfunction of endothelial cells and monocytes, the cellular and molecular consequences of a cytomegaly virus infection in the coronary artery, circulating endothelial precursor cells and vascular repair, the role of VEGF in arteriogenesis, and the role of VEGF and VEGF substitutes and gene therapies to maintain the integrity of the arterial wall. Finally the group is holding a grant on the pharmacogenic and antisense delivery for therapy of restenosis. top