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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Thin-Walled Microvessels in Human Coronary Atherosclerotic Plaques Show Incomplete Endothelial Junctions

Relevance of Compromised Structural Integrity for Intraplaque Microvascular Leakage

Judith C. Sluimer, PhD^_*, Frank D. Kolodgie, PhD, Ann P.J.J. Bijnens, PhD^_*, Kimberly Maxfield, BSc, Erica Pacheco, MSc, Bob Kutys, MSc, Hans Duimel, BSc^_*, Peter M. Frederik, PhD^_*, Victor W.M. van Hinsbergh, PhD, Renu Virmani, MD, PhD and Mat J.A.P. Daemen, MD, PhD^_*,_*

^_* Maastricht University Medical Center, Department of Pathology, CARIM, Maastricht, the Netherlands
CVPath, Gaithersburg, Maryland
VU Medical Center, Department of Physiology, ICAR-VU, Amsterdam, the Netherlands

Manuscript received June 2, 2008; revised manuscript received December 3, 2008, accepted December 8, 2008.

^_* Reprint requests and correspondence: Dr. Mat J. A. P. Daemen, Maastricht University Medical Center, Department of Pathology, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands (Email: Mat.Daemen{at}path.unimaas.nl).

Objectives: This study sought to examine the ultrastructure of microvessels in normal and atherosclerotic coronary arteries and its association with plaque phenotype.

Background: Microvessels in atherosclerotic plaques are an entry point for inflammatory and red blood cells; yet, there are limited data on the ultrastructural integrity of microvessels in human atherosclerosis.

Methods: Microvessel density (MVD) and ultrastructural morphology were determined in the adventitia, intima-media border, and atherosclerotic plaque of 28 coronary arteries using immunohistochemistry for endothelial cells (Ulex europeaus, CD31/CD34), basement membrane (laminin, collagen IV), and mural cells (desmin, alpha-smooth muscle [SM] actin, smoothelin, SM1, SM2, SMemb). Ultrastructural characterization of microvessel morphology was performed by electron microscopy.

Results: The MVD was increased in advanced plaques compared with early plaques, which correlated with lesion morphology. Adventitial MVD was higher than intraplaque MVD in normal arteries and early plaques, but adventitial and intraplaque MVD were similar in advanced plaques. Although microvessel basement membranes were intact, the percentage of thin-walled microvessels was similarly low in normal and atherosclerotic adventitia, in the adventitia and the plaque, and in all plaque types. Intraplaque microvascular endothelial cells (ECs) were abnormal, with membrane blebs, intracytoplasmic vacuoles, open EC-EC junctions, and basement membrane detachment. Leukocyte infiltration was frequently observed by electron microscopy, and confirmed by CD45RO and CD68 immunohistochemistry.

Conclusions: The MVD was associated with coronary plaque progression and morphology. Microvessels were thin-walled in normal and atherosclerotic arteries, and the compromised structural integrity of microvascular endothelium may explain the microvascular leakage responsible for intraplaque hemorrhage in advanced human coronary atherosclerosis.

Key Words: coronary atherosclerosis • angiogenesis • microvascular leakage • junctions • ultrastructure

Abbreviations and Acronyms   EC = endothelial cell   E-FA = thick fibrous cap atheroma with an early core   IEL = internal elastic lamina   IM = intima-media   IT = intimal thickening, normal   L-FA = thick fibrous cap atheroma with late necrotic core   MVD = microvessel density   PIT = pathological intimal thickening   SM = smooth muscle   SMA = smooth muscle actin   SMC = smooth muscle cell   TCFA = thin fibrous cap atheroma   VEGF = vascular endothelial growth factor

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