The microcirculation in atherogenesis.

The term ‘atherosclerosis’ is generally employed for a disease process characterized by the formation of atheromas (fibrofatty intimal plaques) resulting in progressive hardening of the arterial wall, loss of vascular elasticity, and luminal compromise. Different segments of the vascular tree vary in their susceptibility to develop atherosclerotic lesions: atheromas have been described characteristically in middleand large-sized muscular and elastic arteries. Aorta and iliac, coronary and cerebral arteries are considered the prime targets, and so peripheral artery disease, myocardial infarcts, and cerebral infarcts are the most prominent clinical manifestations of the disease. There does not exist one definite ‘microcirculatory manifestation’ of atherosclerosis. Rather, there is an array of different involvements of the microcirculation in distinct processes with relevance to atherosclerosis (Fig. 1). For instance, the microcirculation shows functional alterations that are not necessarily associated with morphological changes of the microcirculatory network per se. This microcirculatory disturbance has been termed ‘downstream dysregulation’. Besides diabetes and hypertension (resulting in various microvascular changes including hyaline arteriolosclerosis; please see respective articles by Hutchins et al. and Tooke et al., in this issue). the microcirculation may be affected by local or systemic pathophysiological challenges such as ischemia/reperfusion injury or the immunologic responses during acute and/or chronic allograft rejection of transplanted organs: transplant-associated accelerated allograft atherosclerosis. One section of this article will cover the microcirculation as it becomes relevant in vase vasorum of complicated atherosclerotic lesions of larger vessels. Finally, this review will address the microcircuIation as a research tool to study cell-cell interaction and other pathophysiologically relevant features of atherogenesis. Arteriosclerosis is considered to be a disease of multifactorial etiology and incompletely understood pathophysiology. Several concepts have been put forward, trying to combine as many aspects as possible into unifying hypotheses. Based on the early proposals made by Virchow in 1847 [ 11, Ross and Glomset [2] formulated the ‘response to injury’ hypothesis of atherogenesis, according to which the sequelae of events originate from an injury to endotheha1 cells (e.g., mechanical, chemical, toxic. viral), leading to denudation or endothelial cell dysfunction. Without going into the details of this hypothesis-which is summarized in a recent update by Ross [3]-the general message of relevance for the understanding of the microcirculatory changes associated with atherosclerosis is the concept of a balance between damaging mechanisms affecting the vessel wall, on the one hand, and the protective defense mechanisms intrinsic to the vessel wall and,/or the components of the blood, on the other hand. This concept covers both functional ‘regulatory’ mechanisms (such as the vasodilator/vasoconstrictor responses) and also morphological aspects (such as oxidative attacks on tnembrane lipids, leading to impaired endothelial cell homeostasis, breakdown of endothelial it&g&y, leakage of fluid and macromolecules. deposition of fat and extracellular matrix, etc.).