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Intracranial atherosclerotic stenosis (ICAS) is a pathological condition characterized by progressive narrowing or complete blockage of intracranial blood vessels caused by plaque formation. This condition leads to reduced blood flow to the brain, resulting in cerebral ischemia and hypoxia. Ischemic stroke (IS) resulting from ICAS poses a significant global public health challenge, especially among East Asian populations. However, the underlying causes of the notable variations in prevalence among diverse populations, as well as the most effective strategies for preventing and treating the rupture and blockage of intracranial plaques, remain incompletely comprehended. Rupture of plaques, bleeding, and thrombosis serve as precipitating factors in the pathogenesis of luminal obstruction in intracranial arteries. Pericytes play a crucial role in the structure and function of blood vessels and face significant challenges in regulating the Vasa Vasorum (VV)and preventing intraplaque hemorrhage (IPH). This review aims to explore innovative therapeutic strategies that target the pathophysiological mechanisms of vulnerable plaques by modulating pericyte biological function. It also discusses the potential applications of pericytes in central nervous system (CNS) diseases and their prospects as a therapeutic intervention in the field of biological tissue engineering regeneration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The pathophysiology of pulmonary hypertension (PH) is not fully understood. Here, we tested the hypothesis that hypoxic perfusion of the vasa vasorum of the pulmonary arterial (PA) wall causes PH. Young adult pig lungs were explanted and placed into a modified ex vivo lung perfusion unit (organ care system, OCS) allowing the separate adjustment of parameters for mechanical ventilation, as well as PA perfusion and bronchial arterial (BA) perfusion. The PA vasa vasorum are branches of the BA. The lungs were used either as the control group ( n = 3) or the intervention group ( n = 8). The protocol for the intervention group was as follows: normoxic ventilation and perfusion (steady state), hypoxic BA perfusion, steady state, and hypoxic BA perfusion. During hypoxic BA perfusion, ventilation and PA perfusion maintained normal. Control lungs were kept under steady-state conditions for 105 min. During the experiments, PA pressure (PAP) and blood gas analysis were frequently monitored. Hypoxic perfusion of the BA resulted in an increase in systolic and mean PAP, a reaction that was reversible upon normoxic BA perfusion. The PAP increase was reproducible during the second hypoxic BA perfusion. Under control conditions, the PAP stayed constant until about 80 min of the experiment. In conclusion, the results of the current study prove that hypoxic perfusion of the vasa vasorum of the PA directly increases PAP in an ex situ lung perfusion setup, suggesting that PA vasa vasorum function and wall ischemia may contribute to the development of PH. NEW & NOTEWORTHY Hypoxic perfusion of the vasa vasorum of the pulmonary artery directly increased pulmonary arterial pressure in an ex vivo lung perfusion setup. This suggests that the function of pulmonary arterial vasa vasorum and wall ischemia may contribute to the development of pulmonary hypertension.

Objective: The pre-collecting and collecting lymph vessels have smooth muscle cells, and sufficient perfusion is vital to maintain their function. Although the vasa vasorum of the collecting lymph vessels (VVCL) have been histologically investigated, little is known about their physiology. This study aimed to investigate the relationship between morphology and blood flow of the VVCL in lymphoedematous limbs., Methods: Medical records of lower extremity lymphoedema patients who underwent video capillaroscopy observation during supermicrosurgical lymphaticovenous anastomosis (LVA) surgery were reviewed. The collecting lymph vessels, dissected for LVA, were examined under video capillaroscopy (GOKO Bscan-ZD, GOKO Imaging Devices Co., Japan) with a magnification of 175x and 620x. Blood flow velocity of the VVCL was calculated by measuring the red blood cell movement using software (GOKO-VIP ver. 1.0.0.4, GOKO Imaging Devices Co., Japan). Based on the video capillaroscopy findings, the VVCL were grouped according to their morphology; the VVCL morphology types and blood flow velocity were then compared according to the lymphosclerosis severity grade., Results: Sixty-seven lymph vessels in 20 lower extremity lymphoedema patients were evaluated, including s0 in 19 (28.4%), s1 in 34 (50.7%), s2 in 10 (14.9%), and s3 in four (6.0%) lymph vessels. The VVCLs were grouped into four types: type 1 (n = 4), type 2 (n = 37), type 3 (n = 19), and type 4 (n = 7). Blood flow velocity of the VVCL ranged 0 - 189.3 μm/sec (average 26.40 μm/sec). There were statistically significant differences in VVCL morphology (p < .001) and blood flow velocity (p < .001) according to lymphosclerotic severity., Conclusion: Vasa vasorum of the collecting lymph vessels could be grouped into four types with different characteristics. Morphological and physiological changes of the VVCL were related to sclerotic changes of the collecting lymph vessels., (Copyright © 2023 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

The arterial vasa vasorum is a specialized microvasculature that provides critical perfusion required for the health of the arterial wall, and is increasingly recognized to play a central role in atherogenesis. Cardio-metabolic disease (CMD) (including hypertension, metabolic syndrome, obesity, diabetes, and pre-diabetes) is associated with insulin resistance, and characteristically injures the microvasculature in multiple tissues, (e.g., the eye, kidney, muscle, and heart). CMD also increases the risk for atherosclerotic vascular disease. Despite this, the impact of CMD on vasa vasorum structure and function has been little studied. Here we review emerging information on the early impact of CMD on the microvasculature in multiple tissues and consider the potential impact on atherosclerosis development and progression, if vasa vasorum is similarly affected.

Vascular stenting is a common intervention for the treatment for atherosclerotic plaques. However, stenting still has a significant rate of restenosis caused by intimal hyperplasia formation. In this study, we evaluate whether stent overexpansion leads to Vasa Vasorum (VV) compression, which may contribute to vascular wall hypoxia and restenosis. An idealized multilayered fibroatheroma model including Vasa Vasorum was expanded by three coronary stent designs up to a 1.3:1 stent/artery luminal diameter ratio (exp1.1, exp1.2, exp1.3) using a finite element analysis approach. Following Poiseuille's law for elliptical sections, the fold increase in flow resistance was calculated based on VV compression in the Intima (Int), Media (Med) and Adventitia (Adv). The VV beneath the plaque experiences the smallest degree of compression, while the opposite wall regions are highly affected by stent overexpansion. The highest compressions for Adv, Med and Int at exp1.1 are 60.7, 65.9, 72.3%, at exp1.2 are 62.1, 67.3, 73.5% and at expp1.3 are 63.2, 68.7, 74.8%. The consequent fold increase in resistance to flow for Adv, Med and Int at exp1.1 is 3.3, 4.4, 6.6, at exp1.2 is 3.5, 4.7, 7.2 and at exp1.3 is 3.8, 5.1, 7.9. Stent overexpansion induces significant VV compression, especially in the Intima and Media layers, in agreement with previously observed Media necrosis and loss in elasticity after stenting. The observed steep increase in flow resistance suggests the blood flow and associated oxygen delivery would drop up to five times in the Media and almost eight in the Intima, which may lead to intimal hyperplasia and restenosis.

Objectives: This study used optical coherence tomography to investigate the mechanism of false lumen (FL) formation in spontaneous coronary artery dissection (SCAD) by studying: 1) differences between fenestrated and nonfenestrated SCAD; 2) vasa vasorum density; and 3) light attenuation characteristics of the FL., Background: SCAD is an increasingly recognized cause of acute coronary syndromes, characterized by FL formation and compression of the true lumen (TL). The mechanisms underlying FL formation remain poorly understood., Methods: A total of 65 SCAD patients (68 vessels) who underwent acute OCT imaging as part of routine clinical care were included. Images were classified by the absence or presence of a connection (fenestration) between the TL and FL. Indexed measurements of TL stenosis, external elastic lamina (EEL) area, FL area, and light attenuation of the FL were assessed. Vasa vasorum densities of SCAD cases were compared with those in control non-SCAD myocardial infarction cases., Results: In nonfenestrated cases, there was significantly larger expansion of the EEL area (9.1% vs. -1.9%; p <0.05) and a larger FL area (73.6% vs. 53.2%, respectively; p <0.05) in dissected segments. No significant differences were found between vasa vasorum density in SCAD and those in control subjects. The FL contents were heterogeneous but attenuated less light than whole blood or thrombus (4.28 ± 0.55 mm -1 vs. 5.08 ± 0.56 mm -1 ; p < 0.05; vs. 4.96 ± 0.56 mm -1 ; p < 0.05)., Conclusions: These observational data suggest that the absence of a fenestration leads to increased FL pressure and compression of the TL. Although vasa vasorum may still be implicated in pathogenesis, increased vasa vasorum density could be an epiphenomenon of vascular healing., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Background: Hypoxia and low pulmonary arterial (PA) blood flow stimulate the development of systemic-to-pulmonary collateral blood vessels, which can be an adverse factor when performing the Fontan operation. The aim of this study was to use optical coherence tomography (OCT) to elucidate the morphological changes in PA vasculature after creation of a bidirectional cavopulmonary connection (BCPC) in children., Methods: This prospective study evaluated PA wall thickness and development of PA vasa vasorum (VV) in the distal PA of eight patients (BCPC group, 1.3 ± 0.3 years) and 20 age-matched children with normal pulmonary artery hemodynamics and morphology (Control group, 1.4 ± 0.3 years). VV development was defined by the VV area ratio, defined as the VV area divided by the adventitial area in cross-sectional images., Results: There was no significant difference in PA wall thickness between the BCPC and control groups (0.12 ± 0.03 mm vs. 0.12 ± 0.02 mm, respectively). The VV area ratio was significantly greater in the BCPC group than in the Control group (14.5 ± 3.5% vs. 5.3 ± 1.6%, respectively; p<0.0001)., Conclusion: OCT is a promising new tool for evaluating PA pathology, including the development of VV in patients after BCPC., Competing Interests: The authors have declared that no competing interests exist.

Objective: Neoangiogenesis is pathophysiologically related to atherosclerotic plaque growth and vulnerability. We examined the in vivo performance of a computational method using contrast-enhanced intravascular ultrasound (CE-IVUS) to detect and quantify aortic wall neovascularization in rabbits. We also compared these findings with histological data., Methods: Nine rabbits were fed with a hyperlipidemic diet. IVUS image sequences were continuously recorded before and after the injection of a contrast agent. Mean enhancement of intensity of a region of interest (MEIR) was calculated using differential imaging algorithm. The percent difference of MEIR before and after the injection of microbubbles (d&#95;MEIR) was used as an index of the density of plaque or/and adventitial neovascularization. Aortic segments were excised for histological analysis., Results: CE-IVUS and histological analysis were performed in 11 arterial segments. MEIR was significantly increased (~20%) after microbubble injection (from 8.1±0.9 to 9.7±1.8, p=0.016). Segments with increased VV/neovessels in the tunica adventitia (histological scores 2 and 3) had significantly higher d&#95;MEIR compared with segments with low presence of VV/neovessels (score 1); 40.5±22.9 vs. 8±14.6, p=0.024, respectively., Conclusion: It is possible to detect VV or neovessels in vivo using computational analysis of CE-IVUS images, which is in agreement with histological data. These findings may have critical implications on vulnerable plaque assessment and risk stratification.

Background: Antiproliferative drugs in drug eluting stents (DES) are associated with complications due to impaired re-endothelialization. Additionally, adventitial neovascularization has been suggested to contribute to in-stent restenosis (ISR). Since Vascular Endothelial Growth Factors (VEGFs) are the key mediators of angiogenesis, we investigated feasibility and efficacy of local gene therapy for ISR utilizing soluble decoy VEGF receptors to reduce biological activity of adventitial VEGFs., Method: Sixty-nine adult WHHL rabbit aortas were subjected to endothelial denudation. Six weeks later catheter-mediated local intramural infusion of 1.5x10e10 pfu adenoviruses encoding soluble VEGF Receptor-1 (sVEGFR1), sVEGFR2, sVEGFR3 or control LacZ and bare metal stent implantation were performed in the same aortic segment. Marker protein expression was assessed at 6d in LacZ cohort. Immunohistochemistry, morphometrical analyses and angiography were performed at d14, d42 and d90., Results: Transgene expression was localized to adventitia. All decoy receptors reduced the size of vasa-vasorum at 14d, AdsVEGFR2 animals also had reduced density of adventitial vasa-vasorum, whereas AdsVEGFR3 increased the density of vasa-vasorum. At d42, AdsVEGFR1 and AdsVEGFR2 reduced ISR (15.7 ± 6.9% stenosis, P < 0.01 and 16.5 ± 2.7%, P < 0.05, respectively) vs. controls (28.3 ± 7.6%). Moreover, AdsVEGFR-3 treatment led to a non-significant trend in the reduction of adventitial lymphatics at all time points and these animals had significantly more advanced neointimal atherosclerosis at 14d and 42d vs. control animals., Conclusions: Targeting adventitial neovascularization using sVEGFR1 and sVEGFR2 is a novel strategy to reduce ISR. The therapeutic effects dissipate at late follow up following short expression profile of adenoviral vectors. However, inhibition of VEGFR3 signaling accelerates neoatherosclerosis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Myocardial bridge (MB) is a myocardial bundle through which coronary segment tunnels and could compress coronary arteries causing myocardial ischemia. However, the characteristic structural findings of MB remain to be fully elucidated. Recently, we demonstrated that optical coherence tomography (OCT) enables us to visualize adventitial vasa vasorum (VV) formation in humans. In this study, we examined adventitial VV formation at the coronary segment with MB in humans using OCT., Methods: We examined 15 consecutive patients with suspected angina pectoris and MB in the left anterior descending (LAD) coronary arteries but no angiographic coronary stenosis. MB was detected on coronary angiography as a segment with milking effect. We performed intracoronary OCT imaging along the entire LAD. Morphometric analysis was performed at MB and proximal/distal segments at every 1mm., Results: OCT examination showed the absence of adventitial VV formation at MB in the LAD, while VV was clearly noted at both the proximal and distal reference segments. Adventitial VV area was significantly less at MB compared with the proximal or distal references., Conclusions: These results with OCT imaging indicate that coronary segments with MB lack adventitial VV formation in humans, suggesting that MB could influence morphological and functional changes of the coronary artery., (Copyright © 2017. Published by Elsevier B.V.)

Vasa vasorum are blood microvessels which penetrate the adventitia and outer layers of the media of large blood vessels, supplying them with nutrients and oxygen. A growing body of evidence suggests that vasa vasorum play a central role in the pathogenesis of atherosclerosis. In this review, we will make a case for the role of microvascular dysfunction in the initiation of disease. When seen through this lens, new therapeutic opportunities for prevention can be envisioned. In particular, we discuss how targeting the cellular metabolism and epigenetic machinery of vasa vasorum neovessels could be harnessed to render vasa vasorum endothelial cells less sensitive to atherogenic stimuli., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There is considerable global demand for three-dimensional (3D) functional tissues which mimic our native organs and tissues for use as in vitro drug screening systems and in regenerative medicine. In particular, there has been an increasing number of patients who suffer from arterial diseases such as arteriosclerosis. As such, in vitro 3D arterial wall models that can evaluate the effects of novel medicines and a novel artificial graft for the treatment are required. In our previous study, we reported the rapid construction of 3D tissues by employing a layer-by-layer (LbL) technique and revealed their potential applications in the pharmaceutical fields and tissue engineering. In this study, we successfully constructed a 3D arterial wall model containing vasa vasorum by employing a LbL technique for the first time. The cells were coated with extracellular matrix nanofilms and seeded into a culture insert using a cell accumulation method. This model had a three-layered hierarchical structure: a fibroblast layer, a smooth muscle layer, and an endothelial layer, which resembled the native arterial wall. Our method could introduce vasa vasorum into a fibroblast layer in vitro and the 3D arterial wall model showed barrier function which was evaluated by immunostaining and transendothelial electrical resistance measurement. Furthermore, electron microscopy observations revealed that the vasa vasorum was composed of single-layered endothelial cells, and the endothelial tubes were surrounded by the basal lamina, which are known to promote maturation and stabilization in native blood capillaries. These models should be useful for tissue engineering, regenerative medicine, and pharmaceutical applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 814-823, 2017., (© 2016 Wiley Periodicals, Inc.)

It has been reported that coronary vasa vasorum is associated with plaque vulnerability, and low-echoic structures in grayscale intravascular ultrasound (IVUS) are consistent pathologically with vasa vasorum. However, the association of low-echoic structures with plaque composition and no-reflow phenomenon during percutaneous coronary intervention (PCI) is unclear. We investigated plaque composition in virtual histology IVUS (VH-IVUS) and no-reflow phenomenon during PCI of low-echoic structures.A total of 106 lesions being treated by VH-IVUS before PCI were included in this study. Low-echoic structure was defined as a small tubular structure exterior to media without a connection to the vessel lumen in ≥ 3 consecutive crosssectional IVUS images. Lesions with low-echoic structures were found in 42% (45/106).Lesions with low-echoic structures were more prevalent in acute coronary syndrome (ACS) patients (53% [24/45] versus 20% [12/61], P < 0.001), had more positive remodeling (49% [22/45] versus 21% [13/61], P = 0.003), a larger number of VH-IVUS derived thin-cap fibroatheromas (VH-TCFAs) (0.64 ± 0.53 versus 0.05 ± 0.22, P < 0.001), more VH-TCFAs with a baseline plaque burden of 70% or more and minimal luminal area of 4.0 mm(2) or less (29% [13/45] versus 2% [1/61], P < 0.001), and more frequent no-reflow phenomenon after stent implantation and more final TIMI flow grade 0/1/2 (38% [17/45] versus 5% [3/61], P < 0.001; 9% [4/45] versus 0% [0/61], P = 0.03) than lesions without low-echo structures.Lesions with low-echoic structures in grayscale IVUS had high plaque vulnerability and were more prevalent in ACS patients, positive remolding, and VH-TCFAs, and they had more frequent no-reflow phenomenon during PCI than lesions without low-echoic structures.

Autologous saphenous veins are commonly used for the coronary artery bypass grafting even if they are liable to progressive patency reduction, known as 'vein graft disease'. Although several cellular and molecular causes for vein graft disease have been identified using in vivo models, the metabolic cues induced by sudden interruption of vasa vasorum blood supply have remained unexplored. In the present manuscript, we describe the design of an ex vivo culture system allowing the generation of an oxygen gradient between the luminal and the adventitial sides of the vein. This system featured a separation between the inner and the outer vessel culture circuits, and integrated a purpose-developed de-oxygenator module enabling the trans-wall oxygen distribution (high oxygen level at luminal side and low oxygen level at the adventitial side) existing in arterialized veins. Compared with standard cultures the bypass-specific conditions determined a significant increase in the proliferation of cells around adventitial vasa vasorum and an elevation in the length density of small and large caliber vasa vasorum. These results suggest, for the first time, a cause-effect relationship between the vein adventitial hypoxia and a neo-vascularization process, a factor known to predispose the arterialized vein conduits to restenosis.

Purpose: To investigate the origin of "corkscrew" collateral vessels around the occluded popliteal artery in patients with Buerger disease by Doppler ultrasound (US) and magnetic resonance (MR) imaging in tandem with digital subtraction angiography (DSA)., Materials and Methods: Between January 2013 and June 2015, 42 patients diagnosed with Buerger disease were identified retrospectively. Patients in whom occlusion of the popliteal artery was found on DSA of the lower extremity were subjected to Doppler US and MR imaging prospectively. Fifteen of 42 patients were identified as having the required characteristics, of whom 10 participated in the present study., Results: Ten patients with occlusion of the popliteal artery were selected for inclusion, and 12 lower limbs of these patients were investigated. The study cohort comprised one woman and nine men with a mean age of 41 years ± 10 (standard deviation; range, 39-58 y). Corkscrew collateral vessels identified on DSA examinations were also identified on secondary imaging (Doppler US and MR imaging) in all patients except one in whom the popliteal artery was reconstituted after short-segment occlusion. The origin of the corkscrew collateral vessels was identified as the vasa nervorum of the tibial nerve in nine patients., Conclusions: Data from the present study suggest that corkscrew collateral vessels at the knee level in patients with Buerger disease originate from the vasa nervorum of the tibial nerve rather than the vasa vasorum of the popliteal artery if the latter is occluded., (Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.)

The aortic wall is perfused by the adventitial vasa vasorum (VV). Tissue hypoxia has previously been observed as a manifestation of enlarged abdominal aortic aneurysms (AAAs). We sought to determine whether hypoperfusion of the adventitial VV could develop AAAs. We created a novel animal model of adventitial VV hypoperfusion with a combination of a polyurethane catheter insertion and a suture ligation of the infrarenal abdominal aorta in rats. VV hypoperfusion caused tissue hypoxia and developed infrarenal AAA, which had similar morphological and pathological characteristics to human AAA. In human AAA tissue, the adventitial VV were stenotic in both small AAAs (30-49 mm in diameter) and in large AAAs (> 50 mm in diameter), with the sac tissue in these AAAs being ischemic and hypoxic. These results indicate that hypoperfusion of adventitial VV has critical effects on the development of infrarenal AAA.

Background: Previous studies have suggested that vasa vasorum (VV) is associated with plaque progression and vulnerability., Objectives: The aim of this study was to investigate the relationship between coronary neovascularization structures and plaque characteristics., Methods: We included 53 patients who underwent optical coherence tomography to observe the proximal left anterior descending coronary artery. Patients were classified into 5 groups according to lesion characteristics: normal; fibrous plaque (FP); fibroatheroma (FA); plaque rupture (PR); and fibrocalcific plaque (FC). We defined signal-poor tubuloluminal structures recognized in cross-sectional and longitudinal profiles located in adventitial layer as VV, and within plaque as intraplaque neovessels. Two types of longitudinal microvascular structure (external running and internal running) and a particular type of intraplaque neovessels (a coral tree pattern) were noted. All VV and intraplaque neovessels were manually segmented followed by quantification with Simpson method., Results: Among the groups, there was significant difference (expressed as median [interquartile range (IQR)]) in VV volume (normal: 0.329 [IQR: 0.209 to 0.361] mm(3), FP: 0.433 [IQR: 0.297 to 0.706] mm(3), FA: 0.288 [IQR: 0.113 to 0.364] mm(3), PR: 0.160 [IQR: 0.141 to 0.193] mm(3), and FC: 0.106 [IQR: 0.053 to 0.165] mm(3); p = 0.003) and intraplaque neovessels volume (normal: 0.00 [IQR: 0.00 to 0.00] mm(3), FP: 0.00 [IQR: 0.00 to 0.00] mm(3), FA: 0.028 [IQR: 0.019 to 0.041] mm(3), PR: 0.035 [IQR: 0.026 to 0.042] mm(3), and FC: 0.010 [IQR: 0.005 to 0.014] mm(3); p < 0.001). Significant differences were observed in the prevalence of the internal running (normal: 0.0%, FP: 28.6%, FA: 40.0%, PR: 70.0%, and FC: 40.0%; p = 0.032) and the coral tree pattern (normal: 0.0%, FP: 7.1%, FA: 40.0%, PR: 80.0%, and FC: 10.0%; p < 0.01). The VV volume correlated with fibrous plaque volume (r = 0.71; p < 0.01)., Conclusions: VV increase with fibrous plaque volume and intraplaque neovessels with particular structures are associated with plaque vulnerability. Imaging for microvasculature could become a new window for plaque vulnerability., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary adventitia harbors a wide variety of components, such as inflammatory cells and vasa vasorum (VV). Adventitial VV initiates the development of coronary artery diseases as an outside-in supply route of inflammation. We have recently demonstrated that drug-eluting stent implantation causes the enhancement of VV formation, with extending to the stent edges in the porcine coronary arteries, and also that optical frequency domain imaging (OFDI) is capable of visualizing VV in humans in vivo. However, it remains to be fully validated whether OFDI enables the precise measurement of VV formation in pigs and humans., Methods and Results: In the pig protocol, a total of 6 bare-metal stents and 12 drug-eluting stents were implanted into the coronary arteries, and at 1 month, the stented coronary arteries were imaged by OFDI ex vivo. OFDI data including the measurement of VV area at the stent edge portions were compared with histological data. There was a significant positive correlation between VV area on OFDI and that on histology (R=0.91, P<0.01). In the human protocol, OFDI enabled the measurement of the VV area at the stent edges after coronary stent implantation in vivo., Conclusions: These results provide the first direct evidence that OFDI enables the precise measurement of the VV area in coronary arteries after stent implantation in pigs and humans.

Background: The importance of adventitial inflammation has been implicated for the pathogenesis of coronary artery disease. However, the roles of adventitial changes in drug-eluting stent (DES)-induced coronary hyperconstriction remain largely unknown. In the present study, this issue in pigs in vivo with a special reference to adventitial vasa vasorum (VV) formation and Rho-kinase activation, a central mechanism of coronary vasospasm, was examined., Methods and Results: Each animal received a sirolimus-eluting stent (SES) and a biolimus A9-eluting stent (BES), one in the left anterior descending and another in the left circumflex coronary arteries in a randomized manner (n=18). After 1, 3 and 6 months, coronary vasomotion was examined. At 1 month, coronary vasoconstriction to serotonin was significantly enhanced at the SES edges as compared with the BES edges (SES, 52±7% vs. BES, 22±3%, P<0.01), which was equally prevented by a selective Rho-kinase inhibitor, hydroxyfasudil. A significant difference in vasoconstriction between SES and BES was sustained for 6 months. A micro-CT showed VV augmentation at the SES site, extending to the proximal and distal edges. Immunostainings demonstrated that VV formation, macrophage infiltration in the adventitia and Rho-kinase expressions/activation were significantly enhanced at the SES edges as compared with the BES edges., Conclusions: The DES with durable polymers enhances VV formation and inflammation in the adventitia, associating with the pathogenesis of DES-induced coronary hyperconstriction through Rho-kinase activation in pigs in vivo.

Objective: Endothelial dysfunction is an early manifestation of atherosclerosis. Inflammation and vasa vasorum play a pivotal role in the pathophysiology of plaque initiation, development, and complications. Optical coherence tomography allows high-resolution imaging of tissue microstructure. Therefore, the aim of this study was to test the hypothesis that segments with endothelial dysfunction show macrophages and vasa vasorum in patients with early coronary artery disease., Approach and Results: Optical coherence tomography images were obtained from 40 patients with mild coronary atherosclerosis who underwent coronary endothelial function assessment. Optical coherence tomography findings, including macrophages and microchannels, were evaluated in 76 coronary segments corresponding to those in endothelial response to acetylcholine. Coronary artery diameter change in response to acetylcholine was more severe in segments showing macrophages (-17.7±14.7% versus -6.3±13.9%; P<0.01) and microchannels (-15.9±15.9% versus -6.4±13.5%; P<0.01) than those without. There were increasing trends of the prevalence of macrophages and microchannels with endothelial dysfunction as stratified by quartiles of coronary artery diameter change (P<0.01 and P=0.02 for trend, respectively). In particular, segments with both macrophages and microchannels (n=12) tended to have worse endothelial function than those with macrophages alone (n=15) and microchannels alone (n=15; -22.1±14.6% versus -10.9±15.6% and -10.9±15.6%; P=0.07 and P=0.06, respectively)., Conclusions: Epicardial endothelial dysfunction was associated with optical coherence tomography -identified macrophages and microchannels in mild coronary atherosclerosis. The current study further supports the role of inflammation and vasa vasorum proliferation in the early stage of coronary atherosclerosis., (© 2014 American Heart Association, Inc.)

Angiogenic expansion of the vasa vasorum (VV) is an important contributor to pulmonary vascular remodeling in the pathogenesis of pulmonary hypertension (PH). High proliferative potential endothelial progenitor-like cells have been described in vascular remodeling and angiogenesis in both systemic and pulmonary circulations. However, their role in hypoxia-induced pulmonary artery (PA) VV expansion in PH is not known. We hypothesized that profound PA VV neovascularization observed in a neonatal calf model of hypoxia-induced PH is due to increased numbers of subsets of high proliferative cells within the PA adventitial VV endothelial cells (VVEC). Using a single cell clonogenic assay, we found that high proliferative potential colony-forming cells (HPP-CFC) comprise a markedly higher percentage in VVEC populations isolated from the PA of hypoxic (VVEC-Hx) compared with control (VVEC-Co) calves. VVEC-Hx populations that comprised higher numbers of HPP-CFC also demonstrated markedly higher expression levels of CD31, CD105, and c-kit than VVEC-Co. In addition, significantly higher expression of CD31, CD105, and c-kit was observed in HPP-CFC vs. the VVEC of the control but not of hypoxic animals. HPP-CFC exhibited migratory and tube formation capabilities, two important attributes of angiogenic phenotype. Furthermore, HPP-CFC-Co and some HPP-CFC-Hx exhibited elevated telomerase activity, consistent with their high replicative potential, whereas a number of HPP-CFC-Hx exhibited impaired telomerase activity, suggestive of their senescence state. In conclusion, our data suggest that hypoxia-induced VV expansion involves an emergence of HPP-CFC populations of a distinct phenotype with increased angiogenic capabilities. These cells may serve as a potential target for regulating VVEC neovascularization.

Background: Kawasaki Disease (KD) involves a diffuse and systemic vasculitis of unknown etiology that mainly affects infants and children. Although a considerable number of analyses of the clinical, histopathological and molecular biological details underlying the mechanism responsible for the development of coronary arterial lesions, it is still poorly understood.The purpose of this study was to analyze the state of angiogenesis, vasculogenesis and the distribution of blood vessels using an animal model of KD like vasculitis. We investigated the involvement of the vasa vasorum from the adventitia in the vascular involvement and the development of the disease state by performing sequential histopathology, scanning electron microscopy (SEM) and micro computed tomography (CT) studies using a murine model of vasculitis induced by the Candida albicans water-soluble fraction (CAWS)., Methods: To prepare the animal model of KD like vasculitis, CAWS was intraperitoneally injected into C57BL/6N mice for five consecutive days as reported by Ohno et al. We observed the changes of the vasa vasorum at the aorta and the orifices of the coronary arteries by SEM and micro CT, and also compared the neovascularization at the media and adventitia of the aorta by an immunohistochemical analysis., Results: As previously reported, obvious inflammation was detected two weeks after the injection of CAWS, and also intimal thickening was observed three weeks after the injection. We found that the vasa vasorum in the adventitia of the aorta was increased in the model mice. The vasa vasorum started increasing one week after the injection of CAWS, before any obvious vasculitis was microscopically detected., Conclusion: The present results indicate that the vasculitis in Kawasaki disease starts as a disorder of the vasa vasorum.

To evaluate the potential of whole-body CT to detect localized areas of decreased or increased vascularity in coronary arterial walls. We used both microsphere embolization of coronary artery vasa vasorum to generate small areas of hypoperfusion and surrounding hyperperfusion of the arterial wall and diet-induced hypercholesterolemia. As a stimulus for localized angiogenesis, such as occurs in early plaque formation in the coronary arterial wall, microspheres were injected selectively into the LAD coronary artery lumens of anesthetized pigs. Fourteen pigs (acute) then had a segment of their LAD harvested during injection of contrast medium and snap-frozen for subsequent cryo-static micro-CT. An additional thirteen pigs (chronic) were allowed to recover, fed a high cholesterol diet and 3 months later were again anesthetized and a segment of the LAD artery harvested and scanned. The spatial distribution of the contrast agent within the arterial wall was measured in contiguous micro-CT images at right angles to the lumen axis with the area of wall in each cross-sectional image being approximately (0.1 mm)(3) in size. In the acute animals there were no localized areas of increased contrast around the hypoperfused embolized perfusion territories in the arterial wall, but in the chronic animals the hypoperfused areas were surrounded by increased contrast. These results suggest that CT might be able to detect localized regions of increased vascularity in the arterial wall as an indicator of early atherosclerotic stimulation of vasa vasorum proliferation.

Atherosclerotic plaque rupture with luminal thrombosis is the most common mechanism responsible for the majority of acute coronary syndromes and sudden coronary death. The precursor lesion of plaque rupture is thought to be a thin cap fibroatheroma (TCFA) or "vulnerable plaque". TCFA is characterised by a necrotic core with an overlying thin fibrous cap (≤65 μm) that is infiltrated by macrophages and T-lymphocytes. Intraplaque haemorrhage is a major contributor to the enlargement of the necrotic core. Haemorrhage is thought to occur from leaky vasa vasorum that invades the intima from the adventitia as the intima enlarges. The early atherosclerotic plaque progression from pathologic intimal thickening (PIT) to a fibroatheroma is thought to be the result of macrophage infiltration. PIT is characterised by the presence of lipid pools which consist of proteoglycan with lipid insudation. The conversion of the lipid pool to a necrotic core is poorly understood but is thought to occur as a result of macrophage infiltration which releases matrix metalloproteinase (MMPs) along with macrophage apoptosis that leads to the formation of a acellular necrotic core. The fibroatheroma has a thick fibrous cap that begins to thin over time through macrophage MMP release and apoptotic death of smooth muscle cells converting the fibroatheroma into a TCFA. Other causes of thrombosis include plaque erosion which is less frequent than plaque rupture but is a common cause of thrombosis in young individuals especially women <50 years of age. The underlying lesion morphology in plaque erosion consists of PIT or a thick cap fibroatheroma. Calcified nodule is the least frequent cause of thrombosis, which occurs in older individuals with heavily calcified and tortious arteries., (Copyright © 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The vasa vasorum are unique networks of vessels that become angiogenic in response to changes in the vessel wall. Structural studies, using various imaging modalities, show that the vasa vasorum form a plexus of microvessels during the atherosclerotic disease process. The events that stimulate vasa vasorum neovascularization remain unclear. Anti-angiogenic molecules have been shown to inhibit/regress the neovascularization; they provide significant insight into vasa vasorum function, structure, and specific requirements for growth and stability. This review discusses evidence for and against potential stimulators of vasa vasorum neovascularization. Anti-angiogenic rPAI-123, a truncated isoform of plasminogen activator inhibitor-1 (PAI-1) stimulates a novel pathway for regulating plasmin activity. This mechanism contributes significantly to vasa vasorum regression/collapse and is discussed as a model of regression., (Copyright © 2013 Elsevier Inc. All rights reserved.)

No-touch (NT) saphenous vein (SV) grafts are superior to SVs harvested by the conventional technique (CT), with a patency comparable with the internal thoracic artery (ITA). Preservation of the vasa vasorum is implicated in the success of NT harvesting. We compared the vasa vasorum and endothelial nitric oxide synthase (eNOS) in NT SV with ITA and radial artery (RA) grafts. Skeletonized SV (SSV) was also analyzed. The NT SV had a higher number and larger vasa vasorum compared with ITA (P = .0001) and RA (P = .0004) that correlated with eNOS protein. Activity of eNOS in SSV grafts was significantly lower than NT SV grafts (P = 004). Since a high proportion of the vasa vasorum are removed in SSV using the CT, we suggest that preservation of the vasa vasorum and eNOS-derived NO contributes to the high patency for NT as compared with SSV grafts.

Objective: Neovascularization of human atherosclerotic plaques is implicated in plaque progression and destabilization, although its functional implications are yet unresolved. Here, we aimed to elucidate functional and morphological properties of plaque microvessels in mice in vivo., Methods and Results: Atherosclerotic carotid arteries from aged (>40 weeks) apolipoprotein E-deficient mice were imaged in vivo using multiphoton laser scanning microscopy. Two distinct groups of vasa vasorum microvessels were observed at sites of atherosclerosis development (median diameters of 18.5 and 5.9 μm, respectively), whereas microvessels within the plaque could only rarely be found. In vivo imaging showed ongoing angiogenic activity and injection of fluorescein isothiocyanate-dextran confirmed active perfusion. Plaque vasa vasorum showed increased microvascular leakage, combined with a loss of endothelial glycocalyx. Mean blood flow velocity in plaque-associated vasa vasorum was reduced by ±50% compared with diameter-matched control capillaries, whereas mean blood flow was reduced 8-fold. Leukocyte adhesion and extravasation were increased 6-fold in vasa vasorum versus control capillaries., Conclusions: Using a novel in vivo functional imaging strategy, we showed that plaque-associated vasa vasorum were angiogenically active and, albeit poorly, perfused. Moreover, plaque-associated vasa vasorum showed increased permeability, reduced blood flow, and increased leukocyte adhesion and extravasation (ie, characteristics that could contribute to plaque progression and destabilization).

There is an increased body of evidence to suggest that the vasa vasorum play a major role in the progression and complications of vulnerable plaque leading to acute coronary syndrome. We propose that detecting changes in the flow in the vascular wall by intravascular ultrasound signals can quantify the presence of vasa vasorum. The results obtained in a porcine model of atherosclerosis suggest that intravascular ultrasound-based estimates of blood flow in the arterial wall can be used in vivo in a clinical research setting to establish the density of vasa vasorum as an indicator of plaque vulnerability., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Vasa vasorum (VV) are microscopic vases that perfuse the vessel's wall; arteries and veins. Many recent researches support the opinion that VV have a significant role in aortic pathology. The VV, or 'the vessels of the vessels', form a network of microvessels that lie in the adventitia and penetrate the outer media of the host vessel wall. Although the importance of the VV in providing nutritional support is not well known, obstruction of blood flow through these vessels has been implicated in the pathogenesis of many cardiovascular diseases such as aortic intramural hematoma, aortic aneurysm, and acute or chronic aortic dissection. Although the proliferation of VV due to atherogenic stimuli is controversial, experimental and clinical studies strongly suggest the potential of VV in vascular proliferative disorders. It seems that the rupture of VV is implicated in intramural hematoma, which can develop in acute aortic dissection. In this review article, we would like to stress the anatomy and mainly the pathophysiology, and the implication of VV in the acute and chronic aortic pathologies., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Aims: Atherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis., Methods and Results: We examined apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-)/OX40L-double-deficient (ApoE(-/-)/OX40L(-/-)) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. We also treated high-fat-fed ApoE(-/-) mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assay in vivo were significantly reduced in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. Finally, when high-fat-fed ApoE(-/-) mice were transplanted with bone marrow cells from either wild-type or OX40L(-/-) mice, the extent of aortic atheroma was comparable between the two groups., Conclusion: These results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.

Objectives and Design: To establish whether in diabetic patients with peripheral artery obstructive disease (PAOD) vasa vasorum (vv) neoangiogenesis is altered with increased arterial damage., Materials: Thirty-three patients with PAOD and critical lower limb ischaemia, 22 with type II diabetes., Methods: Immunohistochemistry for endothelial cell markers (CD34 and von Willebrand Factor); real-time reverse transcription polymerase chain reaction (RT-PCR) to quantify arterial wall expression of vascular endothelial growth factor (VEGF); enzyme-linked immunosorbent assay (ELISA) to assess blood VEGF; flow cytometry to detect circulating endothelial cells (CECs)., Results: Patients with PAOD and diabetes have a higher frequency (60% vs. 45%) of advanced atherosclerotic lesions and a significant reduction (p = 0.0003) in CD34(+) capillaries in the arterial media. Adventitial neoangiogenesis was increased equally (CD34(+) and vWF(+)) in all patients. Likewise, all patients have increased CEC and VEGF concentration in the blood as well as in-situ VEGF transcript expression., Conclusions: Patients with PAOD have remarkable arterial damage despite increased in-situ and circulating expression of the pro-angiogenic VEGF; a dysfunctional vv angiogenesis was seen in diabetics which also showed a higher frequency of parietal damage; it is suggested that in diabetic arterial wall, injury is worsened by vv inability to finalise an effective VEGF-driven arterial wall neoangiogenesis., (Copyright 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Because heart originates from primitive endocardial tube (ventral aorta) embryologically, coronary arteries that supply this tube can be thought as "cardiac vasa vasorum" like arterial vasa vasorum that supply peripheral arteries. Coronary arteries have vasodilative reaction to noradrenaline, different from the most arteries that show vasoconstriction. This phenomenon is similar to vasa vasorum that are insensitive to noradrenaline and has its own vasoregulation. Coronary arteries can supply blood from epicardium, myocardium to endocardium under normal physiological conditions. But heart having a significant myocardial hypertrophy can be susceptible to subendocardial ischemia because the metabolic demands of hypertrophic myocardium cannot be met by a parallel increase of coronary myocardial capillaries. This peculiar characteristic of coronary arteries is similar to vasa vasorum that give rise to ischemic necrosis of media of the host vessel under chronic hypertension. Inherency of coronary arteries is the same endarteries as vasa vasorum. Coronary arteries have many smooth muscle fibers than elastic fibers in media, which protect them to collapse during systole to some extent. This feature also is similar to vasa vasorum. The above similarities support the hypothesis that coronary arteries are a kind of vasa vasorum., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

The vasa vasorum form a network of microvasculature that originate primarily in the adventitial layer of large arteries. These vessels supply oxygen and nutrients to the outer layers of the arterial wall. The expansion of the vasa vasorum to the second order is associated with neovascularization related to progression of atherosclerosis. Immunohistological analysis of human plaques from autopsied aortas have defined plaque progression and show a significant correlation with vasa vasorum neovascularization. Recent technological advances in microcomputed tomography have enabled investigation of vasa vasorum structure and function in nondiseased large arteries from pigs and dogs. Smaller mammals, particularly mice with genetic modifications that enable disease development, have been used extensively to study the vasa vasorum in diseased vessels. Despite the fact that most mouse models that are used to study atherosclerosis are unable to develop plaque to the extent found in humans, studies in both humans and mice underscore the importance of angiogenic vasa vasorum in progression of atherosclerosis. Those who have examined the vasa vasorum in occluded vessels of nondiseased pigs and dogs find that inhibition of the vasa vasorum makes the animals atheroprone. Atherosclerosis is a multifactorial disease. There is increasing evidence that factors, produced in response to changes in the arterial wall, collaborate with the vasa vasorum to enhance the disease process.

Collateralization of a hemodynamically compromised internal carotid artery (ICA) by the vasa vasorum is rare. We report the serial radiologic findings of an apparent hypertrophied vasa vasorum of the cervical ICA, which was secondary to arterial dissection.

We describe a patient with a symptomatic left giant carotido-ophthalmic aneurysm who initially underwent coil embolization with subtotal obliteration. The patient's symptoms were initially stable, but 1 year later, she presented with a rapidly progressive contralateral visual deficit. Although angiogram showed a stable neck remnant, MR confirmed aneurysm growth and showed a new peripheral hematoma in the wall of the thrombosed aneurysm. Surgical exploration was undertaken, and even after trapping and intra-aneurysmal thrombectomy, constant bleeding was observed from the wall of the thrombosed aneurysm consistent with the vasa vasorum. Bleeding stopped after cauterization and partial resection of the aneurysm dome, and the aneurysm was clipped. The patient's recent visual deficit markedly improved, and the angiogram did not reveal any residue. Giant aneurysms may continue to grow due to a hypertrophic vasa vasorum and subadventitial hemorrhages. Surgery should be considered if complete thrombosis of the aneurysm does not alleviate patient's symptoms.

The adventitia and the outer layers of media of an atherosclerosis-prone arterial wall are vascularized by vasa vasorum. Upon growth of an atherosclerotic lesion in the intima, neovascular sprouts originating from the adventitial vasa vasorum enter the lesion, the local proangiogenic micromilieu in the lesion being created by intramural hypoxia, by increased intramural oxidant stress, and by inflammatory cell infiltration (macrophages, T cells and mast cells). The angiogenic factors present in the lesions include various growth factors, chemokines, cytokines, proteinases, and several other factors possessing direct or indirect angiogenic activities, while the current list of antiangiogenic factors is smaller. An imbalance between endogenous inducers and inhibitors of angiogenesis, with a predominance of the former ones, is essential for the development of neovessels during the progression of the lesion. By providing oxygen and nutrients to the cells of atherosclerotic lesions, neovascularization initially tends to prevent cellular death and so contributes to plaque growth and stabilization. However, the inflammatory cells may induce rupture of the fragile neovessels, and so cause intraplaque hemorrhage and ensuing plaque destabilization. Pharmacological inhibition of angiogenesis in atherosclerotic plaques with ensuing inhibition of lesion progression has been achieved in animal models, but clinical studies aiming at regulation of angiogenesis in the atherosclerotic arterial wall can be designed only after we have reached a firm conclusion about the role of angiogenesis at various stages of lesion development--good or bad.

The purpose of this work was to compare the effects of hypertension and hypercholesterolemia on carotid endothelial function, structure, and vasa vasorum density. Seventeen pigs were randomized to a 12-week normal diet without (n=5), or with renovascular hypertension (HT; n=6), or to a high cholesterol diet (HC; n=6). Carotid arteries were studied by organ chambers (endothelial function) and microcomputed tomography (vasa vasorum), and tissue was processed for Sirius red staining and immunoblotting (vascular endothelium growth factor, endostatin, matrix metalloproteinase-9, and matrix metalloproteinase-2). HC and HT showed reduced vasodilation to acetylcholine as compared with controls, but HT also had a lower response to sodium nitroprusside. In addition, HT showed a higher content of organized collagen fibers and increased intima-media thickness. Vasa vasorum density was increased in HC but not in HT. Both HT and HC showed a proangiogenetic biochemical milieu (higher vascular endothelium growth factor, matrix metalloproteinases, and lower endostatin), but this was more pronounced in HC. Both hypertension and hypercholesterolemia induce endothelial dysfunction in the carotid artery. However, hypertension is also associated with greater fibrosis and vascular wall thickening, which might impair endothelium-independent vasorelaxation and vasa vasorum growth. Hypercholesterolemia is, in turn, associated with vasa vasorum neovascularization. These data suggest that carotid atherosclerosis can evolve through different mechanisms in relation to different risk factors.

Endothelial dysfunction is an established clinical marker of early coronary artery disease and has been shown to be associated with increased cardiovascular morbidity and mortality. New concepts now extend the view of endothelial dysfunction beyond the traditional involvement of the coronary arterial endothelium alone. Recent research indicates that the coronary vessel wall, especially the vasa vasorum, as well as bone marrow-derived endothelial progenitor cells may be subject to proatherosclerotic changes, even before the development of angiographically evident endothelial dysfunction; therefore, "microvascular endothelial dysfunction," which is composed of dysfunction of the vasa vasorum's endothelium as well as "microcellular endothelial dysfunction," reflecting impaired mobilization and function of endothelial progenitor cells, may precede "macrovascular endothelial dysfunction." Vasa vasorum neovascularization, with endothelial leakage and dysfunction increasing influx of proinflammatory and proatherogenic cellular and noncellular substances into the vessel wall, is proposed as one feature of this new concept. In addition, the role of bone marrow-derived endothelial progenitor cells is discussed as are the potential impact of impaired progenitor cell mobilization, release from the marrow, and function in acute and stable coronary artery disease. Finally, potential future therapies are proposed, focusing on interventions that may prevent or diminish the development of the microvascular and microcellular endothelial dysfunction.

The role of vasa vasorum (VV) in atherosclerosis is hotly debated, and new experimental techniques have recently opened an opportunity to take a fresh look at this important topic. Although the proliferation of VV due to atherogenic stimuli is controversial, experimental and clinical evidence strongly suggest the potential of VV in vascular proliferative disorders. In the past, paradigms of atherosclerosis and restenosis have excluded the adventitia and VV in the artery wall due, in part, to a lack of i) appropriate animal models featuring adventitial VV neovascularization, ii) imaging technologies to quantitate adventitial VV and plaque neovascularization and iii) its consequences, concerning information on detectable plaque substrate in vulnerable lesions. VV proliferation is associated with increasing plaque burden and is linked to cellular processes which are critical during the development of atherosclerotic plaques such as inflammation, plaque perfusion and concomitant intraplaque hemorrhage - but the regulation and induction of VV based on pathological settings are poorly understood. This review discusses the current scientific status and its controversies and identifies open research questions.

Cardiovascular disease is associated with the aging of the population, obesity, metabolic syndrome, and diabetes. Therefore, it is important to develop non-invasive imaging systems to detect "at-risk" populations. New data suggest that contrast-enhanced ultrasound (CU) imaging of the carotid arteries enhances luminal irregularities (i.e., ulcers and plaques), improves near-wall, carotid intima-media thickness, and uniquely permits direct, real-time visualization of neovasculature of the atherosclerotic plaque and associated adventitial vasa vasorum. With continued clinical investigation, CU imaging of the carotid artery may afford an effective means to non-invasively identify atherosclerosis in "at-risk" populations while providing new standard for therapeutic monitoring.