Vascular pathology: a pathogenetic challenge for a new millennium

Despite the high level of interest in oncology within contemporary medical research, cardiovascular disease still remains the leading cause of death in modern society. Moreover, its incidence in the developing world is increasing rapidly1. This fact alone makes the topic of vascular pathology a necessary focal point of our diagnostic and research activity as we stand on the threshold of a new century and millennium. It was therefore with great pleasure that the guest editors accepted the call of the Editor-in-Chief of The Journal of Pathology to put together the first annual review issue of the new millennium on this central theme of vascular pathology. A careful look at the authorship underlines the significance of many fields of biomedical endeavour for the progress in blood vessel pathogenesis. Thus, in addition to contributions from traditional university institutes of pathology, both diagnostic and investigative, laboratories are represented which have a strong bias towards molecular pathology within the fields of biochemistry, physiology, pharmacology, molecular biology and internal medicine. This heterogeneity serves to underline both the broad spectrum of interest and the relevance of the multidisciplinary approach to vascular pathology. It is also true that many of the central themes of vascular pathobiology have received new impulses from other spheres of biomedical research, which have not just initiated intriguing intellectual debates, but also raised questions of immense therapeutic relevance, as, for example, the possible role of infectious agents in atherogenesis2, with special focus on Chlamydia pneumoniae3. The fact that a series of clinical trials has been initiated to investigate prospectively the possible efficacy of antibiotics administered over a period of a few months, for example in the so-called WIZARD study on ischaemic cardiovascular disease4, must cause alarm among experts in clinical bacteriology, because of the added risks of micro-organism resistance. The far-reaching implications of this ongoing debate were reason enough for one of the guest editors, Anton Becker (Amsterdam, The Netherlands) with a long-standing research interest in atherosclerosis to review the scientific data critically5. The awarding of the 1998 Nobel Prize for Medicine/Physiology for the pioneering work on the important signalling molecule, nitric oxide (NO)6, much of the knowledge of which derived from vascular physiology, has helped highlight the fascination of the vascular field as an exciting area of biomedical research. The complexity of NO biology is shown by the fact that it can be synthesized by three distinct isoforms of NO-synthase, the activity of which has been well investigated in a variety of cell types, so that a clear picture is beginning to emerge on how NO is involved in numerous vascular disorders from hypertension to severe inflammation. It is fitting that Ulrich Förstermann (Mainz, Germany), a pharmacologist and former co-worker of one of the Nobel laureates, Ferid Murad, should take on the task of reviewing this important topic7. The subject of NO is also relevant to how cells react to oxidative stress, which in the vascular field is of special relevance to the complications of ischaemic injury followed by reperfusion. The massive functional changes occuring in the microcirculation in such circumstances have been reviewed by a leading molecular physiologist, Neil Granger (Louisiana, USA), who also addresses the central themes of remote organ injury and ischaemic preconditioning8. A topic which has gained considerable attention through oncological research is that of apoptosis. Indeed this subject was well discussed in last year's annual review issue, for example under the heading of tumour therapy9. However, apoptosis is also very relevant to any situation of cell turnover, and in the context of vascular disease this is well demonstrated by the atherosclerotic plaque. Mark Kockx (Antwerp, Belgium) has presented a very competent view of how apoptosis is involved in plaque stabilization/destabilization and in doing so has made a critical appraisal of methodological problems inherent in some apoptosis assays10. Another theme which attracts both oncological and non-oncological researchers is how cells interact with each other11, 12. Cell adhesion molecules (CAMs) form an important part of many of the review articles in this issue, although one paper deals specifically with the molecular mechanisms involved in regulating endothelial cell contacts. This important topic, with implications for numerous essential vascular responses, from angiogenesis to permeability and leukocyte emigration, has been reviewed by a scientist actively involved at the forefront of CAM research, Dietmar Vestweber (Münster, Germany)13. An ever-increasing field of activity in pathology is the complications associated with biomaterial applications. As tissue engineering gains momentum14, diagnostic pathologists will be confronted with reactions to highly complex cellular and matrix constructions, designed to replace tissue and organ function. Unfortunately, this sector is populated by only a few pathologists, although vascular disease has been a field of biomaterial application for decades. Part of the reluctance on the part of our profession to play an active role is the additional burden of having to grasp rheological and mechanical principles (for example, compliance mismatch) in order to fathom the pathogenesis of implant-associated disorders. One of the guest editors, Sir Colin Berry (London, UK) has reviewed this for vascular grafts, with special emphasis on how factors derived from the engineering sciences are involved in intimal hyperplasia15. The latter lesion also represents a final common pathway as a response to numerous injuries to the vessel wall, whether it be a further example of a biomaterial, such as a coronary stent, or the disease for which it is employed, namely atherosclerosis itself. It is therefore not surprising that this pathological process has become the focus of intense research activity. Andrew Newby (Bristol, UK) illuminates intima hyperplasia from the molecular standpoint and focuses particularly on the current concepts on how the intima is remodelled through a rapidly initiated turnover of cells and extracellular matrix16. In doing so he discusses the molecular mechanisms underlying the phenotypic change in smooth muscle cells and their subsequent proliferative and migratory activity. Growth factors and matrix metalloproteinases have a central pathogenetic role to play following the key stimuli of injury, inflammation and altered wall stress. Because of the high exposure of oncological themes in pathology as well as in biomedical research generally, there is always the temptation in a publication such as this, on a primarily non-oncological theme, to ‘redress the balance’ by excluding any topic with the slightest hint of neoplasia. This small-minded approach naturally did not feature in our deliberations. In fact, we recalled that malignant tumours were dependent for their well-being on the vascular system and not vice versa (viz. angiogenesis, haematogenous metastasis). The exciting interface between vascular pathology and cancer metastasis has been detailed by Bill Orr (Winnipeg, Canada), who has a long-standing record of investigating how cancer cells interact with the endothelium17. It is evident that the topic of angiogenesis should also be well represented in this annual review issue. Faithful readers will instantly recall that within the past year, this Journal published an excellent critical review dedicated to angiogenesis18. It was nevertheless felt that the annual review issue would be deficient without reference to this fundamental activity of the vascular system. Douglas Thompson (Aberdeen, UK) has updated his previous overview. In addition, the central importance of angiogenesis for vascular pathology is also reflected in the fact that this subject is addressed in many of the other contributions. Very much related to, but nevertheless distinct from the theme of angiogenesis, is that of arteriogenesis, which concerns the expansion of the collateral circulation, with relevance not only for myocardial adaptation to ischaemia, but for other regions of the circulation. Wolfgang Schaper (Bad Nauheim, Germany), a leading authority in this field, concisely presents the evidence for and significance of this important phenomenon, which is only now beginning to receive the broad interest it deserves19. The cover photograph for this issue also merits attention. In the 1999 annual review issue on cancer, the crab was an excellent, unifying choice20. After some deliberation our decision was made in favour of a scanning electron micrograph, signifying the morphological tradition of pathology, focused on a pathogenetic ‘thread’, which pervades much of vascular pathobiology, namely leukocyte–endothelial interactions. It will become evident from many of the individual contributions that this is a recurring theme of centre-stage significance in vessel wall damage, be it in the form of monocyte activity, as in atherosclerosis, or as a result of pathological cross-talk between granulocytes and endothelial cells. This latter pathomechanism is so essential that it features in many articles. We were especially delighted that Peter Ward (Michigan, USA) readily consented to review the field of inflammatory vascular damage, which he has helped shape over a period of many years21. He highlights the underlying molecular mechanisms by which both neutrophils and endothelial cells contribute to the demise of the endothelium, and in doing so provides a useful link to the contributions on NO7, ischaemia-reperfusion injury8, vasculitis22 and sepsis25. In addition to the special focus on co-operativity between neutrophils and endothelial cells, neutrophil-independent mechanisms of vascular damage are also discussed. It is fitting that a presentation on the basic science of leukocyte–endothelial interactions in vascular wall injury should be followed by a critical view of our knowledge on systemic vasculitis. To make a very complex theme manageable within the scope of a single review article, Caroline Savage (Birmingham, UK), a nephrologist, has taken the entity of ANCA-associated systemic vasculitis and discussed its pathogenesis, not only from the point of view of neutrophil-mediated pathomechanisms (proteinases, reactive oxygen species and NO), but also the later involvement of mononuclear cells22. The contribution of underlying immunopathological mechanisms also forms an important part of this review. A further recurring theme throughout the review articles in this issue is the active participation of the endothelium in all disease entities discussed. Endothelial cell functions constitute a delicate balance of opposing actions, which in the physiological situation are strictly controlled. This has led to the metaphor of the ‘face of Janus’23, because the endothelium is capable under pathological circumstances of completely reversing its physiological functions. This is exemplified by the control of haemostasis, a phenomenon which has been known for a very long time. The review by Klaus Preissner (Giessen, Germany) underlines the fact that for the biochemist this topic is far from being a well-trodden path, but instead opens up a completely new vista on the control of vascular function24. Focusing on the expanding field of vascular protease receptors, he demonstrates how these receptor-mediated control mechanisms not only regulate the haemostatic response but are also involved in the signal transduction of other fundamental endothelial functions, including proliferation and adhesion. The penultimate theme is one in which endothelial dysfunction, especially in the microcirculation, is a central pathogenetic factor, namely in the septic state. One of the guest editors, James Kirkpatrick (Mainz, Germany), reviews the evidence for this from clinical, animal experimental and in vitro observations and attempts to show how this is being used as a basis for therapeutic intervention in multiple organ dysfunction syndrome and sepsis25. Nevertheless, major discrepancies still remain between the success in various experimental models and the sobering statistics from contemporary intensive care medicine. Last but not least, Peter Carmeliet (Leuven, Belgium) gives an authorative review of what can be achieved with the help of a modern molecular toolbox. Transgenic technology has gained tremendous momentum in the past few years and is being avidly adopted as a methodology to study not only tumour biology26, 27, but also inflammatory diseases28. Peter Carmeliet's paper on the use of transgenic mouse models in the study of cardiovascular disease gives a foretaste of what direction could be taken in the first years of the next century29. Thus, his review is admirably suited to complete a tour of contemporary vascular pathology themes, which we hope will act as a useful update and also hopefully attract young scientists seeking a challenge for the next millennium. Finally, we would like to express our special gratitude to all authors of this annual review issue for their willingness to take on yet another task with a tight schedule in the midst of numerous responsibilites. It is our sincere hope that this issue will receive wide readership, not only within the ranks of active diagnostic pathologists as well as interested clinicians, but also in the fields of cell and molecular biology, whose contributions to our knowledge of these disease processes cannot be overstated. We feel sure that the study of vascular pathology in the next millennium will be characterized by a high degree of interdisciplinarity, which will not only deepen our understanding of this fascinating field but also, as a consequence, offer new therapeutic approaches.

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