Atherosclerotic Plaque VASA Vasorum in Diabetic Macroangiopathy: WHEN IS Important, but also HOW IS Needed

Thomas Willis in 1678 was the first to describe the outermost layer of larger blood vessels when he authored Pharmaceutice Rationalis.[1] Willis defines small vessels penetrating deeper layers of large vessel walls. In 1969, Frederic Ruysch called “vasa arteriosa” in an illustration the vessels we know now as vasa vasorum (VV),[2] and it was Christian Ludwig who first used the term “vasa vasorum” in 1739.[3] The VVs are a vital microvascular network supporting the outer wall of large blood vessels that provide oxygen and nutrients and concurrently a route for the immune cells to patrol adventitia and perivascular adipose tissue.[4] [5] [6]

VVs have been studied for nearly three- and a-half centuries and our understanding has progressed over a series of fits and starts since the mid-1920s. The 1960s was the first decade to see an exponential increase in the number of publications on VV. Between 1964 and 1966, Clarke described the distribution of VV in several human vessels including the location of medial VV.[7] [8] [9] The VV network within parent arteries and veins follows a similar hierarchy to that of artery–arteriole–capillary, where vessels oriented along the longitudinal axis of the host vessel are known as “first-order” and are similar in size to arterioles; “second-order” vessels in capillary size range branch from first-order vessels and extend circumferentially around the host vessel. First- and second-order VVs contain smooth muscle cell (SMC) layer(s), while smaller second-order (<25 µm) VVs exhibit pericyte coverage with α-smooth muscle expression in subsets.[10] The ratio of first- to second-order VV seems highly important for the proper health of the host vessel. VVs are also able to regulate their own tone,[11] as they are responsive to physiologic and neural stimuli.[12]

Two types of VVs are described in the literature: (1) the first type is the VV interna, which originates from the luminal surface or the media and branches into the adjacent artery wall; and (2) the second type is the VV externa, which is found primarily in the adventitia at its border with the media and originates from various anatomic locations.[13] The amount of VV varies considerably across the blood vessels and is generally higher in veins than in arteries.[14]

The location of VV within larger vessels and the vital function of these vessels demand a better understanding of how they contribute to and/or are influenced by cardiovascular pathologies. For decades, VVs have been implicated, associated, and targeted in the context of various cardiovascular diseases due to the mutual interconnection between angiogenesis and inflammation. The latter underlies many pathophysiological processes linked to thrombosis and atherogenesis, which has been the focus of recent papers.[15] [16] [17]

An increased number of VVs in the adventitia is a characteristic of vascular diseases, including atherosclerosis,[18] [19] restenosis,[20] and hypercholesterolemia.[21] Moreover, VV expansion is intimately associated with neointimal remodeling,[21] while antiangiogenic therapies have tried to inhibit intimal hyperplasia[22] and plaque growth.[23] [24] [25] Correlations of adventitial and perivascular micro-vessels with vascular inflammation, leaky plaque, and neo-vessels are well recognized as important drivers of atherosclerotic progression and ruptured atherosclerotic lesions.[26]

Tissue factor (TF) is the receptor for the coagulation protease factor VIIa (FVIIa), with major roles in pathological activation of coagulation, whereby formation of the TF–FVIIa complex triggers blood coagulation.[27] [28] TF is expressed at high levels in atherosclerotic plaques by both macrophage-derived foam cells and vascular SMCs (VSMCs), as well as extracellular vesicles derived from these cells.[29] TF-mediated activation of coagulation is critically important for arterial thrombosis in the setting of atherosclerotic disease. Moreover, Arderiu et al[30] have demonstrated that endothelial cells (ECs) of new blood vessels within atherosclerotic lesions express both TF and CCL2. CCL2 expression recruits VSMCs to the neo-vessels. This effect of TF in new blood vessel formation is mediated by the ETS1 transcription factor[31] and PAR2-SMAD3 to stabilize these newly formed vessels.[32] Similarly, TF in extracellular vesicles regulates monocyte differentiation and attraction.[33]

Diabetic macroangiopathy, a specific form of accelerated atherosclerosis, is characterized by intra-plaque new vessel formation due to excessive/abnormal neo-vasculogenesis and angiogenesis, increased vascular permeability of the capillary vessels, and tissue edema, resulting in frequent atherosclerotic plaque hemorrhage and plaque rupture. Mechanisms that may explain the premature and rapidly progressive nature of atherosclerosis in diabetes are multiple, and hyperglycemia certainly plays an important role. Hyperglycemia promotes vascular complications by activation of nuclear factor-κB, a key mediator that regulates multiple pro-inflammatory and pro-atherosclerotic target genes in ECs, VSMCs, and macrophages.[34] Inflammation is a key event characterizing and promoting the early steps of atherogenesis in general, and also of diabetic macroangiopathy.[35] [36] [37] Moreover, oxidative and hyperosmolar stresses, and activation of inflammatory pathways triggered by a dysregulated activation of membrane channel proteins aquaporins, have also been recognized as key events.[38] [39]

As might be expected, progress in our understanding of the role of neo-vessels of VV in normal physiology as well as in the evolution of atherosclerotic plaque in the clinical setting has been limited by the lack of experimental tools with sufficient resolution to either directly image VV or otherwise test its functional behavior. Moreover, small laboratory rodents normally lack VV in their arterial vessels. However, vascular injury or atherogenesis in genetically prone laboratory rodents each can promote formation of a reactive, more inflammatory “neovascular” VV at sites of pathologic injury. Development of this usually begins from vessels in the adventitial layer which, as noted, includes not just vessels but resident macrophages, mast cells, B and T-lymphocytes, adipocytes, fibroblasts, and progenitor cells.

In this issue of the journal, Chen et al[40] report a study on neo-vessels on VV in in type 2 diabetic patients with macroangiopathy or without atherosclerosis in femoral artery samples from amputation cases. The study shows that in type 2 diabetic patients with macroangiopathy the density of neovascularization in VV is positively correlated with the number of immune-inflammatory cells in the adventitia and with atherosclerotic lesion development. In addition, these findings associate with adverse cardiovascular events. They compared the VV in the arterial vessel wall of femoral arteries with advanced atherosclerotic disease with samples with only limited atherosclerotic diseases in the lower leg, which were their controls. They correlated the neo-vessel VV density to these two types of lesions and to the presence of inflammatory cells and the clinical history of past cardiovascular events. They showed that the number of macrophages was closely related to higher number of neo-vessels in VV, and not to other inflammatory cell types. The authors propose that the ECs that form the neo-vessels in VV are not completely functional because their junctions are incomplete, and that they do not attract pericytes, leaving channels for where inflammatory factors and cells may promote atherosclerotic formation.

How and what regulates neo-vessel formation on VV in the described conditions by Chen et al[40] remains to be investigated. However, because TF is expressed in ECs of newly formed vessels in atherosclerotic plaques, it might be interesting to investigate TF expression and function on type 2 diabetic patients with macroangiopathy ([Fig. 1]).

Fig. 1 Inflammation and hyperglycemia increase diabetic macroangiopathy. Diabetic macroangiopathy is characterized by intra-plaque new vessel formation due to excessive/abnormal neovasculogenesis and angiogenesis. Increased inflammation and hyperglycemia could promote Wnt5a release from monocyte that through the noncanonical pathway could interact with FZD5 in mECs, increase intracellular Ca2+ release and NF-κB activation, and upregulate TF expression and TF signaling to induce the neo-vessel formation. TF by activating the main transcription factor ETS1 through AKT and ERK1/2 signaling or through a cooperative transcription factor SMAD3 through PAR2 and ERK1/2 may then signal to upregulate CCL2 gene expression and promote the stabilization of the new vessels by attracting SMCs/perycites. NF-κB, nuclear factor kappa B; SMC, smooth muscle cell; TF, tissue factor.

The study by Chen et al, in this issue, suggests that neo-vessel formation in VV of the large arteries is a mechanism for promoting atherosclerosis in the host vessel. Information on neo-vessel formation in VV could help determine the early changes of vascular wall and discriminate which intervention could be the best against the development of atherosclerotic lesions.

Publication History

Received: 22 June 2023

Accepted: 22 June 2023

Accepted Manuscript online:
23 June 2023

Article published online:
24 July 2023

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