Enhanced Vasa Vasorum Formation at Spasm Site　– Coincident Plexus or External Pathogenic Routes? –

The arterial wall is a 3-layered structure composed of intima, media and adventitia. Based on the response-to-injury hypothesis,¹ vessel pathogenesis is thought to start on the luminal side. Therefore, for many years, the adventitia has been misrecognized as merely non-functional connective tissue surrounding the vascular wall, even though the tunica adventitia is the most complex sublayer, comprising fibroblasts, inflammatory cells, progenitor cells, pericytes and endothelial cells of the vasa vasorum, and neurons.² Emerging evidence has revised such traditional viewpoints of the adventitia. Recent studies have revealed that the adventitia plays pivotal roles in cell trafficking, maintaining the vessel wall, controlling lumen size by regulating medial smooth muscle tone, storage of progenitor cells, and regulation of the immune response.² In addition to the adventitia, perivascular adipose tissue adjacent to the adventitia has lately attracted considerable attention. Mazurek et al reported that epicardial adipose tissue is a source of several inflammatory mediators, including interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α, in high-risk patients.³ Nakanishi et al reported that perivascular fat surrounding the coronary artery is associated with coronary plaque vulnerability in patients with coronary artery disease (CAD).⁴ More attention needs to be paid to the external layer of the vessel in vascular pathogenesis. However, the lack of a pathogenic route connecting the outer layer to the interior of the arterial wall has complicated the discussion for a long time.

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The vasa vasorum is a specialized microvasculature normally located in the adventitial layer and maintains the integrity of vessel wall to provide oxygen and nutrients. The vasa vasorum presumably respond to the oxygen and nutrient needs of the vessel walls when supplies are insufficient by diffusion from the lumen because of thickening of the intima.⁵ Therefore, previous ex vivo studies have suggested that the vasa vasorum could play a key role in the development of human atherosclerotic plaques.⁶ Recently, second-generation optical coherence tomography (OCT) has been introduced to the clinical setting and one of its advantages over previous coronary imaging tools is the ability to evaluate the vasa vasorum in vivo.⁷ A recent 3D-OCT study by Taruya et al confirmed that the adventitial vasa vasorum arise from the coronary lumen, penetrate the media/intima and are associated with plaque progression and vulnerability in patients with CAD.⁸ The vasa vasorum are highly likely to be the pathogenic route connecting the external arterial wall surface to the vessel’s interior.

In this issue of the Journal, Nishimiya et al report enhanced adventitial vasa vasorum formation at a focal vasospasm site using OCT.⁹ The results are consistent with their previous report in patients with diffuse-type vasospastic angina.¹⁰ They have also reported rich perivascular fat in vasospastic angina.¹¹ Based on their results, the outside of the vessel wall seems to participate in the pathogenesis of vasospastic angina (Figure). There is debate on the pathogenesis of vasospastic angina.¹² Because the endothelium maintains vascular tone by synthesizing and releasing several vasodilator substances, including prostaglandin I₂ and nitric oxide,¹² endothelial dysfunction has been thought to be the main cause of vasospastic angina. In contrast, Shimokawa and colleagues have proposed that vascular smooth muscle cell (VSMC) hyperreactivity by Rho-kinase activation is the key pathophysiological mechanism for vasospastic angina.¹³ An electron microscopy study by Uchida et al in a swine model showed radial rearrangement of medial VSMCs generated by their own contraction, resulting in medial thickening and folding of the internal elastic lamina to create a piston effect that narrows the lumen.¹⁴ An OCT study reported that patients with vasospastic angina have a larger media thickness with an intimal bump, even when asymptomatic, and intimal gathering by medial constriction creates luminal narrowing during spasm in patients with vasospastic angina.¹⁵ These in vivo observations strongly support that abnormal medial constriction is the main cause of vasospastic angina. Considering that the vasa vasorum are interweaved throughout the layers of the coronary artery,⁸ the results of the current study⁹ could show the link between the exterior of the vessel and the abnormal medial constriction in vasospastic angina.

Figure.

The outside of a coronary artery consists of several possible participants in vasospasm. IL, interleukin; MCP-1, monocyte chemoattractant protein-1; TNF, tumor necrosis factor.

There are several questions and limitations. The cause-effect relationship between enhanced vasa vasorum formation and spasm is unclear. An in vivo OCT study reported that adventitial vasa vasorum formation increases from the early stages of coronary plaque development.⁸ If enhanced vasa vasorum formation were the key to the onset of vasospastic angina, we would encounter many more patients with vasospasm in daily practice. The crosstalk among the rich, perivascular adipose tissue, enhanced vasa vasorum, and abnormal medial constriction should be elucidated. The current OCT assessment of the vasa vasorum has several limitations. Coronary lumen cleaning with X-ray contrast agent is needed to acquire OCT images, but this procedure could collapse some of the vasa vasorum. The current OCT is not able to detect adventitial vasa vasorum through a lipid-rich or large plaque.

The present study was a single-center preliminary study with insufficient participants to make a conclusion. Further studies are necessary to confirm these intriguing findings. Comprehension of the mechanisms underlying enhanced vasa vasorum and vasospasm would provide new therapeutic targets, especially for patients with refractory spasm.

References

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