Endovascular Injury

Although atherosclerotic disease is the major cause of morbidity and mortality in advanced civilizations, other diseases of the vasculature are common and have been modeled in animals.

With the development of interventional techniques to treat cardiovascular disease, especially in the coronary circulation, it has become apparent that the maladaptive response to endovascular injury (clinically referred to as restenosis) is mechanistically distinct from atherosclerosis, although a few features (such as smooth muscle proliferation) are common in both processes. Endovascular injury originally was used experimentally as a means to induce vascular responses, but the widespread use of balloon angioplasty and endovascular stenting has made the modeling of endovascular injury a greater experimental imperative.

Attempts to induce endovascular injury have been made in virtually every laboratory animal. In animals with large-caliber arteries, such as monkeys, pigs, and dogs, the same approaches that are used clinically (balloon injury and stent implantation) are used experimentally. In most cases, the time course and the extent of injury induced are similar to those seen in humans, especially when these techniques are accompanied by high-fat diets or are performed on pre-injured arterial segments. The initial phases of the response to endovas-cular injury consist of endothelial denudation, platelet adhesion, and intravascular thrombosis. The acute phase is followed by medial hyperplasia of smooth muscle cells, with resultant migration and further proliferation within the intima that occurs one to four weeks after injury. During the latter phase of the injury response, matrix deposition and further intimal thickening occur, leading to an eventual return to quiescence, albeit with an obstructive endovascular lesion at the site of injury (Patterson, 2002).

The response to endovascular injury, both in humans and in animal models, is further complicated because arterial remodeling provides an additional influence on the ultimate vascular response. This remodeling, which involves changes in the elastic laminae and adventitia that can either be favorable (outward) or unfavorable (inward) can modulate the extent to which lesions induced by endovascular injury become obstructive. Unfortunately, the mechanisms that regulate this remodeling phase are poorly understood, which emphasizes the need to study and understand this process in animal models.

Owing to the mechanical requirements for endovas-cular injury, large animal models produce more favorable responses that closely mimic the human condition. Injury to nonhuman primates using standard balloon catheter techniques results in a vascular response almost identical to that observed in humans, with early thrombosis and a late remodeling phase. Unfortunately, few centers have access to this approach. Balloon-mediated injury to the Yucatan minipig provides a consistent high-grade lesion, especially when combined with a high-fat diet, and these lesions can themselves be used as further targets for stent implantation (Gal et al., 1990). These characteristics have made the swine model attractive both for studying the pathogenesis of endovascular injury and as a tool for the development of interventional techniques.

One major disadvantage of the aforementioned approaches is the time and expense necessary for large animal studies, not only with respect to the cost of the animals themselves but also attendant costs of instrumentation and anesthesia costs, none of which are trivial. Attempts to create appropriate small animal models of endovascular injury have, therefore, been a high priority. The caliber of blood vessels in New Zealand white rabbits has limited the usefulness of these animals for such approaches, but the larger Giant Flemish rabbits overcome this limitation and have seen some use for this purpose (LeVeen et al., 1982). The rat carotid injury model, in which a balloon is used to damage the endothelium of the carotid artery, produces a characteristic lesion that has been extensively characterized (for example, see Ruef et al. (1999). Unfortunately, the lesion in these animals is limited predominantly to smooth muscle proliferation, and for this reason translation of studies using this approach should be limited to understanding mechanisms for activation of smooth muscle cells. Thrombotic, inflammatory, and remodeling components are largely lacking in this model, which explains why observations of drug effects based on rat carotid injury have not been reproducible in early phase drug development studies in humans.

In spite of the limitations of the rat approach to endo-vascular injury, there have now been numerous attempts to simulate this injury response in mice. The impetus for these efforts stems in part from the ease of use of mice as an animal model from a logistical perspective, but probably even more from the widespread availability of genetically modified mouse strains that allow specific characterization of pathophysiologic mechanisms. The approaches that have been used in mice are varied, and include endolumenal injury with wires to denude endothelium, arterial ligation (particularly of the carotid artery) to induce flow-dependent proliferation and remodeling, and a wide variety of direct arterial injury approaches. These models have been enormously fruitful in eliciting mechanisms of the injury response, particularly with regard to proliferative responses. However, it is essential to keep in mind that the response to injury in these mouse models is limited almost exclusively to medial smooth muscle cell proliferation, which is only one among many components of the endovascular injury response in humans. Thus, these studies must be carefully interpreted. At present, mouse models have limited utility for testing pharmacologic interventions.

Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

Get My Free Ebook


Post a comment