Elimination of Neoangiogenesis for Plaque StabilizationIs There a Role for Local Drug Therapy?
Frank D. Kolodgie, PhD*,
Jagat Narula, MD, PhD, FACC ,2,
Chun Yuan, PhD ,
Allen P. Burke, MD, FACC*,
Aloke V. Finn, MD and
Renu Virmani, MD, FACC*,1,*
* CVPath Institute, Gaithersburg, Maryland
University of California, Irvine, California
University of Washington, Seattle, Washington
Massachusetts General Hospital, Boston, Massachusetts.
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Figure 1 Neovascularization in Stable and Unstable Coronary Plaques
Unstable atherosclerotic plaques thin-cap fibroatheroma (A to C) and rupture (D to F) are associated with marked neoangiogenesis. The microvessels close to the adventitial and medial layers (B and E) tend to be in contact with surrounding smooth muscle cells compared with intimal vessels closer to the lumen, which are characterized by a single lining of luminal endothelium (C and F). The main pathologic feature of the vulnerable plaque is an intact thin fibrous cap heavily infiltrated by macrophages (A). In plaque rupture (D), the fibrous cap is disrupted with a superimposed luminal thrombus. The adventitial vessels in unstable plaques often show perivascular smooth muscle cells (B and E). In contrast, the vasa vasorum close to the necrotic core are abnormal, consisting mostly of endothelial cells overlying a disrupted "leaky" basement membrane. (G to J) Stable plaques, on the other hand, although severely narrowed, contain mostly collagen, proteoglycans, and calcium, and show fewer vasa vasorum in the intima, media, and adventitia. (K) Bar graph showing the mean number of vasa vasorum for stable and unstable plaques. The values within the bars represent the number of lesions examined. Note that unstable thin-cap fibroatheromas (TCFA) and ruptures show significantly greater densities of microvessels compared with stable plaques. Endothelial markers: Ulex europeaus (Ulex) and anti-von Willebrand factor (vWF) antibody immunohistochemical staining; smooth muscle cell (SMC) marker:  -actin. (A, D, and G) Movat pentachrome staining. Modified from Virmani et al. (6). A = adventitia; I = intima; M = media; NC = necrotic core; Th = thrombus.
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Figure 2 Diagram Illustrating Molecules Critical to Angiogenesis and Potential Therapeutic Targets
The scheme highlights the ability of growth factors to positively regulate the "angiogenic switch" to stimulate new vessel formation. Vessel stabilization is mediated by a coordinated response involving platelet-derived growth factor and receptor (PDGR/PDGFR) and angiopoietin (Ang) 1. Modified from Moulton et al. (43). BM = basement membrane; EC = endothelial cell; FGF = fibroblast growth factor; FGFR = fibroblast growth factor receptor; Ig = immunoglobulin; MMP = matrix metalloproteinase; PIGF = placenta growth factor; RGD = arginine-glycine-aspartic acid; Tie-2 = tunica internal endothelial cell kinase; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.
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Figure 3 Diagram Illustrating the Potential Pathologic Outcome After Neovascular Regression of Developing Human Coronary Atheroma
(A) In advanced unstable atheroma, intraplaque vasa vasorum leak, allowing red blood cells (RBCs) to spill into the surrounding microenvironment. Red blood cell membrane-derived cholesterol and associated macrophage infiltration in response to hemorrhage contribute to necrotic expansion. (B) Targeted therapy to eliminate intraplaque microvasculature should reduce plaque burden and necrotic core size by eliminating RBC membrane-derived cholesterol and secondary macrophage response. The alterations in lesion substrate should favor plaque stabilization with a reduction of plaque size. A= adventitia; I= intima; M= media.
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