Atherosclerosis and Angiogenesis: Its Pathophysiological Significance in Humans as Well as in an Animal Model Induced by the Gene Transfer of Vascular Endothelial Growth Factor a

Newly formed blood vessels have been observed in the atherosclerotic plaques of the human coronary arteries.'-' Attention has recently refocused on the role of new blood vessels in the progression and regression of atherosclerotic foci, especially in relation to plaque rupture, thrombus formation, and coronary ~ p a s m . ~ ~ However, there are still some unresolved problems, such as the origin of newly formed blood vessels and the angiogenic machanism(s) in the atherosclerotic intima and their pathophysiologic significance, because there have been a few quantitative studies8 performed so far concerning either the distribution of these new vessels within the atherosclerotic intima or the correlation between the histologic alterations and the preferential occurrence of intimal neovascularization. Moreover, there have been few reports on an animal model of either intimal angiogenesis9 or hemorrhagelo in arteriosclerotic arteries. It is well known that neovascularization is a ubiquitous and vital response in various physiologic and pathologic conditions, such as embryonic development,".'2 the inflammatory-repair process, proliferative diabetic re ti no path^,'^ and the growth of solid These angiogenic processes in vivo may involve various factors, especially growth factors and cytokines. In particular, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF),'9g20 has recently been characterized as an angiogenic factor that is believed to be an endothelialspecific and hypoxia-inducible mitogen, which possesses a heparin-binding affinity