The sections above provide an overview of the many inflammatory and thrombogenic changes that occur in the vasculature during hypercholesterolemia. These include alterations on both the arteriolar and venular sides of the microvasculature, unlike in large vessels where arteries (and not veins) appear to be the primary site of injury during hypercholesterolemia. In addition, the microcirculation responds to hypercholeste-rolemia within 1-2 weeks, whereas in atherosclerosis-prone areas of the aorta and other large arteries, changes are observed only after long-term hypercholesterolemia. Despite these differences, many similarities exist between the mechanisms involved in the microvascular and macrovascular responses to elevated cholesterol levels. These include the induction of CAMs, leukocyte, and platelet recruitment and the release of cytokines/chemokines. Of most relevance to the topic discussed here is the finding that some of the earliest detectable changes in both small and large vessels under hypercholesterolemic conditions are diminished NO bioavailability and the activation of several ROS-generating systems leading to oxidative stress. The demonstration that many of the microvascular alterations are similar to, but occur far in advance ofthe changes in the large vessels, leads to the possibility that the inflammatory and thrombogenic environment experienced during the initial phase of hypercholesterolemia may provide novel mechanistic insights into and may even play a role in the chronic modifications of the macrovasculature during the slow process of atherosclerotic lesion development. However, despite the mounting literature describing the patho-physiological alterations throughout the vasculature during hypercholesterolemia, a link between these two processes has not been investigated to date.
Regardless of the existence (and exact nature) of a link between the events that occur in the microvasculature and macrovasculature during hypercholesterolemia, it is likely that both acute and chronic elevations in blood cholesterol contribute to the cardiovascular consequences of this risk factor. Furthermore, several studies have demonstrated that the early microvascular changes exacerbate the vascular responses to other injuries such as ischemia by enhancing the vulnerability of the vessel wall and circulating cells to other stimuli. This has important implications in the pathogenesis of ischemic diseases in which a role for hypercholesterolemia has been suggested. Hence, therapeutic strategies that are directed against the early inflammatory alterations initiated in the microcirculation by hypercholesterolemia may be valuable in the quest to reduce the high mortality associated with ischemic tissue diseases. Agents that act to maintain the normal physiological balance between ROS and NO in the vascular wall may prove particularly useful in the prevention of ischemic diseases and in the reduction of other atherosclerosis-associated complications.
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