CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Judith C. Sluimer, PhD,
Ann-Pascale J. Bijnens, PhD and
Mat J. Daemen, MD, PhD*
* Department of Pathology, University of Maastricht, Cardiovascular Research Institute Maastricht (CARIM), P.O. Box 5800, 6202 AZ Maastricht, the Netherlands (Email: Mat.Daemen{at}path.unimaas.nl).
In their letter, Dr. Biedermann and colleagues point to the existence of distinct angiogenic events in the intima and adventitia in human atherosclerosis. They also suggest that adventitial angiogenesis might not be driven by local hypoxia, whereas the intima is hypoxic and may drive intimal angiogenesis, as we have shown in our recent paper (1).
In that study, we were not able to analyze the existence of hypoxia in the adventitia because our analysis was restricted to carotid endarterectomy specimen that only contained the intima and small parts of the media. It is known that the adventitia does contain macrophages, which does increase the quest for oxygen, and adventitial microvessels are present. As suggested recently, one reason for adventitial hypoxia might be insufficient perfusion, because the adventitial vessels are very thin walled (J.C. Sluimer et al., unpublished data, March 2008) and may collapse at least in part during the cardiac cycle (2). The true value of this suggestion, however, needs to be determined by the actual quantification of adventitial microvessel flow during the cardiac cycle.
Plaque macrophage hypoxic stress is indeed suggested to be a strong driver of plaque angiogenesis. Although adventitial and plaque angiogenesis may have another driving stimulus, there is a close connection between plaque and adventitial microvessels, because the vast majority of plaque vessels seem to sprout from adventitial microvessels that penetrate through the media, as demonstrated by Virmani et al. (3). This close anatomic connection between adventitial and plaque microvessels might therefore also stimulate angiogenesis in the adventitia, albeit indirectly. We agree with Dr. Biedermann and colleagues that this does not implicate that the reverse—increased adventitial angiogenesis causes increased plaque angiogenesis—is also true. We do support the call and need for adequate visualization technologies able to quantify plaque and adventitial angiogenesis. In vivo imaging of angiogenesis with the use of contrast-enhanced transcutaneous ultrasound sound is promising, as elegantly shown by Shah et al. (4). However, trials with an extended number of human subjects and validation of histological angiogenesis are required. These technologies may then help to elucidate the close pathophysiological connection between intimal and adventitial angiogenesis in human atherosclerosis. Whether or not these technologies are going to be useful to detect specific plaque stages remains to be investigated.
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1. Sluimer JC, Gasc JM, van Wanroij JL, et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis J Am Coll Cardiol 2008;51:1258-1265.[Abstract/Free Full Text]2. Ritman EL, Lerman A. The dynamic vasa vasorum Cardiovasc Res 2007;75:649-658.[Abstract/Free Full Text] 3. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and vulnerability to rupture angiogenesis as a source of intraplaque hemorrhage Arterioscler Thromb Vasc Biol 2005;25:2054-2061.[Abstract/Free Full Text] 4. Shah F, Balan P, Weinberg M, et al. Contrast-enhanced ultrasound imaging of atherosclerotic carotid plaque neovascularization: a new surrogate marker of atherosclerosis? Vasc Med 2007;12:291-297.[Abstract/Free Full Text]
Related Article
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Arterial Microvessels: An Early or Late Sign of Atherosclerosis?
- Barbara C. Biedermann, Blai Coll, Dan Adam, and Steve B. Feinstein
J. Am. Coll. Cardiol. 2008 52: 968.
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