CARDIOVASCULAR NEWS

                            Angiogenesis may promote atherosclerosis
 

     
        
    Endostatin and TNP-470, proteins that are potent inhibitors of primary tumor growth and angiogenesis, have been shown to inhibit neointimal revascularization in mice, according to a study published in Circulation (1999;99:1726-1732).

   Studies show a higher prevalence of neovascularization in lesions with plaque rupture, mural hemorrhage, or unstable angina. Angiogenesis occurs in association with remodeling and protease activation in the surrounding tissues. Therefore, factors that stimulate plaque angiogenesis could also contribute to activities that promote plaque disruption, the event often responsible for myocardial infarction and ischemic stroke.

   To test the hypothesis that intimal neovascularization promotes progression of atherosclerosis, Moulton KS et al conducted a 16-week experiment involving 73 mice fed a high-cholesterol diet, to induce substantial atherosclerosis. Using immunohistochemistry and transmission electron microscopy, they demonstrated that intimal capillaries occur in advanced lesions of apolipoprotein E–deficient mice. Animals were treated with endostatin or TNP-470 from age 32 to 48 weeks (late-stage experiment) or from 6 to 22 weeks (early-stage experiment). Plaque involvement was measured at the aortic origin.

   They found that long-term treatment with recombinant murine endostatin or TNP-470 significantly reduced further progression of atherosclerosis without affecting cholesterol levels. Those on the drugs averaged 85% less plaque buildup in their aortas than did the controls. The inhibition of plaque growth was associated with a decreased incidence of intimal neovascularization. However, the inhibitory effects of both endostatin and TNP-470 were less pronounced during early atherogenesis.

   The authors conclude that, whereas their study cannot provide conclusive evidence for causality, their findings provide strong support for the hypothesis that intimal vessels contribute to the progression of atherosclerosis.

   The research is exciting in that it raises the possibility that a new category of drugs, the angiogenesis inhibitors, may represent a whole new paradigm for strategies to prevent atherosclerosis and its complications. At the same time, it presents an enigma because current studies show that drugs that promote angiogenesis in the heart muscle can relieve the effects of atherosclerosis. The study of Moulton et al raises the possibility that angiogenesis could also make the underlying disease worse by promoting the growth of plaque.
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