The program and invited speakers addressed the issue of how representative are animal models of thrombosis and vascular disease of the respective human pathologies. Speakers were selected to discuss spontaneous atherosclerosis, resterosis, venous thrombosis and angiogenesis.

The first speaker was Dr. John MacGregor. He reported that the mechanism implicated in the initiation and perpetuation of vascular lesions and their subsequent rupture leading to thrombus formation and total lumen occlusion remains poorly understood. In an effort to investigate such mechanisms his laboratory selected the use of ApoE deficient mice (generated in the laboratory of Dr. Maeda in Chapel Hill, NC), and compared them to C57BL6 wild type, fed a fat or a chow diet. The work focused on the quantitative expression of major adhesion molecules (ICAM-1, VCAM-1, PECAM-1, P-selectin) on the aortic arch of ApoE deficient mice compared to controls (C57BL6). Immunohistochemistry and Northern blots were used to assay the levels of these adhesion molecules at the endothelial cell level or by the whole vessel. Results show modulation of the level of expression of these adhesion molecules at different stages of vascular lesions in ApoE deficient mice. A similar type of result has been observed for human tissue samples. However, no plaque rupture and/or thrombotic occlusion have been observed for these ApoE animals. Great caution has to be taken in interpreting the data observed in the mouse ApoE model. Further work needs to be performed to humanize the ApoE deficient mouse model.

Dr. J.J. Badimon reported on experimental studies of cell cycle inhibition as a therapeutic strategy to decrease coronary restenosis following stenting. Rapamycin was found to inhibit smooth muscle cell proliferation in pig coronary arteries by a direct effect on p27, a negative regulator of cell proliferation, rather than by an apoptosis-related mechanism.

Direct comparisons with data in ApoE KO mice in terms of markers of proliferation/apoptosis were discussed. More research is needed because intra-stent restinosis remains a significant problem in clinical revascularization.

Dr. M. Levi presented the results of a comprehensive review of the literature on animal models of venous thrombosis. In general, experimental venous thrombosis studies have been useful to determine if experimental agents are useful for the inhibition of thrombus formation. However, they have been of lesser utility in dose-finding and comparative pharmacology studies. Discussion followed on species differences regarding pharmacokinetics and coagulation/fibrinolytic system. Research is needed to develop new methods that can provide a clear insight in the etiology of venous thrombosis.

Dr. L. Drouet described the characteristics and utility of a large animal model of chronic venous thrombosis. Thrombi with the same morphologic characteristics as chronic human venous thrombi developed in Gortex grafts implanted in pig external jugular veins, although the distal normal segments did not thrombose. Studies of anticoagulant therapy in this model indicated that heparin was more effective than low molecular weight heparin and low-dose hirudin was ineffective.

Existing models of venous thrombosis, and namely the Wessler model (and derivatives) are:

• studying only the acute thrombotic reactivity for a few hours (while patients have clinical manifestations of thrombosis after days of evolution of the thrombotic process),.
• developed in small rodents (rabbit, rats, etc.) whose flow condition (due to vessel size) are different from human pathology.

A model of chronic venous thrombosis in the pig seems of relevance because the coagulation system of this animal is fairly well known and quite similar to the human system and this animal is accepted as a good model of arterial pathology. Ultrastructural examination shows, as in human thrombosis, an onion skin like structure of the thrombus. It is formed with several layers of dense platelet deposits alternating with layers of fibrin network imprisoning various amounts of red blood cells. The rate of occlusion was 100%.

Dr. P. Carmielet described studies on embryonic and neonatal angiogenesis in mice. He showed data on the role of VEGF in angiogenesis. VEGF knockout mice were found to have defective vascular sprouting. VEGF 121 mutant mice were observed to have a significant decrease in the density of coronary blood vessels. These mice had decreased intramyocardial blood flow and subendocardial ischemia, and they died prematurely of heart failure. Placental growth factor (PLGF) was also found to interact with VEGF in the differentiation of large blood vessels. PLGF seems to play a role in pathological angiogenesis while VEGF seems to play a role both in physiological and pathological angiogenesis. VEGF was found to increase myocardial capillary formation in wild type mice but not in UPA knockout mice.

Dr. G. J. Johnson reported that the Subcommittee report titled "The Utility of Animal Models in the Preclinical Study of Interventions to Prevent Human Coronary Artery Restesosis: Analysis and Recommendations" was recently published in Thrombosis and Haemostasis.

Dr Badimon reported that because the content of the document was of interest to other scientific communities, the editors of Circulation were contacted. They showed interest and asked for a document that possibly could be published as an editorial.

Finally, Dr. Badimon, as the Chair of the Subcommittee, proposed new tasks for the next year. Due to the lack of models specifically addressing the pathophysiology of venous thrombosis, a consensus document on this issue will be prepared by Drs. Levi, Drovet, Johnson, and Badimon. The plan is to have a preliminary draft circulated by January 2000 and a final draft ready for presentation at the next SSC meeting. It will be submitted for approval at a later date.

This year we had a large attendance at our SSC meeting (over 100 participants).

Next year we plan to focus on models of pulmonary embolism and on coagulation factors in animal models