Plaque Neovascularization Is Increased in Ruptured Atherosclerotic Lesions of Human Aorta

Abstract

Background-Growth of atherosclerotic plaques is accompanied by neovascularization from vasa vasorum microvessels extending through the tunica media into the base of the plaque and by lumen-derived microvessels through the fibrous cap. Microvessels are associated with plaque hemorrhage and may play a role in plaque rupture. Accordingly, we tested this hypothesis by investigating whether microvessels in the tunica media, the base of the plaque, and the fibrous cap are increased in ruptured atherosclerotic plaques in human aorta. Methods and Results-Microvessels, defined as CD34-positive tubuloluminal capillaries recognized in cross-sectional and longitudinal profiles, were quantified in 269 advanced human plaques by bicolor immunohistochemistry. Macrophages/T lymphocytes and smooth muscle cells were defined as CD68/CD3-positive and ␣-actin-positive cells. Total microvessel density was increased in ruptured plaques when compared with nonruptured plaques (Pϭ0.0001). Furthermore, microvessel density was increased in lesions with severe macrophage infiltration at the fibrous cap (Pϭ0.0001) and at the shoulders of the plaque (Pϭ0.0001). In addition, microvessel density was also increased in lesions with intraplaque hemorrhage (Pϭ0.04) and in thin-cap fibroatheromas (Pϭ0.038). Logistic regression analysis identified plaque base microvessel density (Pϭ0.003) as an independent correlate to plaque rupture. Conclusions-Thus, neovascularization as manifested by the localized appearance of microvessels is increased in ruptured plaques in the human aorta. Furthermore, microvessel density is increased in lesions with inflammation, with intraplaque hemorrhage, and in thin-cap fibroatheromas. Microvessels at the base of the plaque are independently correlated with plaque rupture, suggesting a contributory role for neovascularization in the process of plaque rupture. (Circulation.

Coronary Plaque Characteristics in Patients With Diabetes Mellitus Who Presented With Acute Coronary Syndromes

“…In our results, in the culprit rupture group, the prevalence of microvessels was higher in patients with DM than in those without. This finding is in line with pathology studies that reported that patients with DM had increased microvessel density, which indicates plaque progression evolving to plaque rupture 29, 30. In contrast, in the culprit rupture group, the prevalence of lipid‐rich plaque, macrophage accumulation, and cholesterol crystals was not different between patients with and without DM.…”

Endothelial α ν β 3 Integrin–Targeted Fumagillin Nanoparticles Inhibit Angiogenesis in Atherosclerosis

“…25 The pathophysiological role of plaque neovascularization includes: (1) permitting plaque growth beyond a wall thickness that limits nutrient diffusion; (2) conducting inflammatory cells and lipoproteins into lesions; and (3) contributing to plaque instability and rupture. 3,26 We have recently reported specific noninvasive detection of molecular epitopes associated with angiogenesis with the use of ␣ ␤ 3 -targeted paramagnetic nanoparticles in hyperlipidemic New Zealand White rabbits. 11 In the present study, we extend that finding and further demonstrate that ␣ ␤ 3 -targeted paramagnetic nanoparticles can deliver fumagillin and elicit a marked antiangiogenic response with a minimal drug dosage.…”

“…32 Careful microscopic study of plaque neovasculature further suggests that the highest levels were associated with ruptured lesions and lipid-rich plaques, whereas the lowest microvascular densities were associated with stable, fibrocalcific lesions. 3 Noninvasive quantification of microvascular density as a surrogate marker of atherosclerotic plaques using ␣ ␤ 3 -targeted paramagnetic nanoparticles integrated over small or large segments of vasculature could provide quantitative estimates of intramural disease burden and severity. In cases of rapidly advancing disease, the local delivery of potent antiangiogenic agents might acutely inhibit plaque progression and afford more opportunity for traditional therapeutic approaches, such as HMG-CoA reductase inhibitors, to provide long-term maintenance of the antineovascular effects.…”

“…1 Extensive neovascular proliferation within atherosclerotic plaques is prominent within "culprit" lesions clinically associated with unstable angina, myocardial infarction, and stroke. [2][3][4] Plaque angiogenesis has been suggested to promote plaque growth, intraplaque hemorrhage, 5 and lesion instability.Magnetic resonance (MR) molecular imaging of focal angiogenesis in vivo with integrin-targeted paramagnetic contrast agents was reported with perfluorocarbon nanoparticles 6 -8 and liposomes. 9 Subsequently, we have developed MRI and postprocessing techniques to permit molecular imaging of the diffuse proliferating neovasculature associated with atherosclerotic plaque development.…”

“…1 Extensive neovascular proliferation within atherosclerotic plaques is prominent within "culprit" lesions clinically associated with unstable angina, myocardial infarction, and stroke. [2][3][4] Plaque angiogenesis has been suggested to promote plaque growth, intraplaque hemorrhage, 5 and lesion instability.…”