Segmental heterogeneity of vasa vasorum neovascularization in human coronary atherosclerosis.
OBJECTIVE
Our aim was to investigate the role of coronary vasa vasorum (VV) neovascularization in the progression and complications of human coronary atherosclerotic plaques.


BACKGROUND
Accumulating evidence supports an important role of VV neovascularization in atherogenesis and lesion location determination in coronary artery disease. VV neovascularization can lead to intraplaque hemorrhage, which has been identified as a promoter of plaque progression and complications like plaque rupture. We hypothesized that distinctive patterns of VV neovascularization and associated plaque complications can be found in different stages of human coronary atherosclerosis.


METHODS
Hearts from 15 patients (age 52+/-5 years, mean+/-SEM) were obtained at autopsy, perfused with Microfil (Flow Tech, Inc., Carver, Massachusetts), and subsequently scanned with micro-computed tomography (CT). The 2-cm segments (n=50) were histologically classified as either normal (n=12), nonstenotic plaque (<50% stenosis, n=18), calcified (n=10) or noncalcified (n=10) stenotic plaque. Micro-CT images were analyzed for VV density (number/mm2), VV vascular area fraction (mm2/mm2), and VV endothelial surface fraction (mm2/mm3). Histological sections were stained for Mallory's (iron), von Kossa (calcium), and glycophorin-A (erythrocyte fragments) as well as endothelial nitric oxide synthase, vascular endothelial growth factor, and tumor necrosis factor-alpha.


RESULTS
VV density was higher in segments with nonstenotic and noncalcified stenotic plaques as compared with normal segments (3.36+/-0.45, 3.72+/-1.03 vs. 1.16+/-0.21, p<0.01). In calcified stenotic plaques, VV spatial density was lowest (0.95+/-0.21, p<0.05 vs. nonstenotic and noncalcified stenotic plaque). The amount of iron and glycophorin A was significantly higher in nonstenotic and stenotic plaques as compared with normal segments, and correlated with VV density (Kendall-Tau correlation coefficient 0.65 and 0.58, respectively, p<0.01). Moreover, relatively high amounts of iron and glycophorin A were found in calcified plaques. Further immunohistochemical characterization of VV revealed positive staining for endothelial nitric oxide synthase and tumor necrosis factor-alpha but not vascular endothelial growth factor.


CONCLUSIONS
Our results support a possible role of VV neovascularization, VV rupture, and intraplaque hemorrhage in the progression and complications of human coronary atherosclerosis.
Division of Cardiovascular Diseases, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Mario
M
Gössl
Daniele
D
Versari
Heike A
HA
Hildebrandt
Thomas
T
Bajanowski
Giuseppe
G
Sangiorgi
Raimund
R
Erbel
Erik L
EL
Ritman
Lilach O
LO
Lerman
Amir
A
Lerman
D001344:Autopsy; D002114:Calcinosis / Q000473:pathology; D002118:Calcium / Q000032:analysis; D023921:Coronary Stenosis / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006021:Glycophorins / Q000032:analysis; D006470:Hemorrhage / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007501:Iron / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D012421:Rupture; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014651:Vasa Vasorum / Q000737:chemistry / Q000000981:diagnostic imaging / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D055114:X-Ray Microtomography
C409972:GYPA protein, human; D006021:Glycophorins; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007501:Iron; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D002118:Calcium