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Vasculogenic properties of adventitial Sca-1+CD45+ progenitor cells in mice: a potential source of vasa vasorum in atherosclerosis.

ABSTRACT: The cellular origins of vasa vasorum are ill-defined and may involve circulating or local progenitor cells. We previously discovered that murine aortic adventitia contains Sca-1+CD45+ progenitors that produce macrophages. Here we investigated whether they are also vasculogenic. In aortas of C57BL/6 mice, Sca-1+CD45+ cells were localised to adventitia and lacked surface expression of endothelial markers (<1% for CD31, CD144, TIE-2). In contrast, they did show expression of CD31, CD144, TIE-2 and VEGFR2 in atherosclerotic ApoE-/- aortas. Although Sca-1+CD45+ cells from C57BL/6 aorta did not express CD31, they formed CD31+ colonies in endothelial differentiation media and produced interconnecting vascular-like cords in Matrigel that contained both endothelial cells and a small population of macrophages, which were located at branch points. Transfer of aortic Sca-1+CD45+ cells generated endothelial cells and neovessels de novo in a hindlimb model of ischaemia and resulted in a 50% increase in perfusion compared to cell-free control. Similarly, their injection into the carotid adventitia of ApoE-/- mice produced donor-derived adventitial and peri-adventitial microvessels after atherogenic diet, suggestive of newly formed vasa vasorum. These findings show that beyond its content of macrophage progenitors, adventitial Sca-1+CD45+ cells are also vasculogenic and may be a source of vasa vasorum during atherogenesis.

SUBMITTER: Toledo-Flores D

PROVIDER: S-EPMC6513996 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Correlation of Adventitial Vasa Vasorum with Intracranial Atherosclerosis: A Postmortem Study.

Project description:Background and purposeVasa vasorum (VV) have been believed to be rare or non-existent in small-caliber intracranial arteries. In a series of human cerebral artery specimens, we identified and examined the distribution of VV in association with co-existing intracranial atherosclerosis.MethodsWe obtained cerebral artery specimens from 32 consecutive autopsies of subjects aged 45 years or above. We scrutinized middle cerebral artery (MCA), vertebral artery (VA), and basilar artery (BA) for the presence of adventitial VV. We described the distribution of VV, and the characteristics of co-existing atherosclerotic lesions.ResultsAmong 157 intracranial arteries, adventitial VV were present in 74 of the 157 specimens (47%), involving MCA (n=13, 18%), BA (n=14, 19%), and VA (n=47, 64%). Although qualitatively these 74 adventitial VV distributed similarly in arteries with or without atherosclerotic lesions (disease-free arteries n=4/8; arteries of pre-atherosclerosis n=17/42; and arteries of progressive atherosclerosis n=53/107), the presence of adventitial VV in intracranial VA was associated with a heavier plaque load (1.72±1.66 mm2 vs. 0.40±0.32 mm2, P<0.001), severer luminal stenosis (25%±21% vs. 12%±9%, P=0.002), higher rate of concentric lesions (79% vs. 36%, P=0.002), and denser intraplaque calcification (44% vs. 0%, P=0.003). Histologically, intracranial VA with VV had a larger diameter (3.40±0.79 mm vs. 2.34±0.58 mm, P<0.001), thicker arterial wall (0.31±0.13 mm vs. 0.23±0.06 mm, P=0.002), and a larger intima-media (0.19±0.09 mm vs. 0.13± 0.04 mm, P=0.003) than VA without VV.Conclusions Our study demonstrated the distribution of adventitial VV within brain vasculature and association between vertebral VV and progressive atherosclerotic lesions with a heavier plaque load and denser intraplaque calcification.

| S-EPMC6186920 | biostudies-literature

Hypoperfusion of the Adventitial Vasa Vasorum Develops an Abdominal Aortic Aneurysm.

Project description: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.

| S-EPMC4550325 | biostudies-literature

Contrast-Enhanced Ultrasound Imaging Quantification of Adventitial Vasa Vasorum in a Rabbit Model of Varying Degrees of Atherosclerosis.

Project description:This study used an atherosclerotic rabbit model to investigate the feasibility of quantifying adventitial vasa vasorum (VV) via contrast-enhanced ultrasound (CEUS) imaging to identify early atherosclerosis. Recent evidence has linked adventitial VV with atherosclerotic plaque progression and vulnerability. A growth in VV density has been detected preceding intimal thickening and even endothelial dysfunction. In our study, carotid atherosclerosis rabbit models were used, and animals underwent CEUS imaging at the end of the atherosclerotic induction period. Normalized maximal video-intensity enhancement (MVE) was calculated to quantify VV density. After CEUS imaging, animals were euthanized, and their carotids were processed for histopathological analysis following staining for CD31 and VEGF. Adventitial normalized MVE increased as atherosclerosis progressed (p < 0.001), and normalized MVE also progressed, demonstrating a linear correlation with histological findings (r = 0.634, p < 0.001 for VEGF-positive; r = 0.538, p < 0.001 for CD31-positive). Thus, we histologically validated that CEUS imaging can be used to quantify the development of adventitial VV associated with atherosclerosis progression. This method can be used for monitoring the VV to detect early atherosclerosis.

| S-EPMC5539241 | biostudies-literature

The influence of sleep apnea syndrome and intermittent hypoxia in carotid adventitial vasa vasorum.

Project description:Subjects with sleep apnea-hypopnea syndrome (SAHS) show an increased carotid intima-media thickness. However, no data exist about earlier markers of atheromatous disease, such as the proliferation and expansion of the adventitial vasa vasorum (VV) to the avascular intima in this setting. Our aim was to assess carotid VV density and its relationship with sleep parameters in a cohort of obese patients without prior vascular events. A total of 55 subjects evaluated for bariatric surgery were prospectively recruited. A non-attended respiratory polygraphy was performed. The apnea-hypopnea index (AHI) and the cumulative percentage of time spent with oxygen saturation below 90% (CT90) were assessed. Serum concentrations of soluble intercellular adhesion molecule 1, P-selectin, lipocalin-2 and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. Contrast-enhanced carotid ultrasound was used to assess the VV density. Patients with SAHS (80%) showed a higher adventitial VV density (0.801±0.125 vs. 0.697±0.082, p = 0.005) and higher levels of sVCAM-1 (745.2±137.8 vs. 643.3±122.7 ng/ml, p = 0.035) than subjects with an AHI lower than 10 events/hour. In addition, a positive association exist between mean VV density and AHI (r = 0.445, p = 0.001) and CT90 (r = 0.399, p = 0.005). Finally, in the multiple linear regression analysis, female sex, fasting plasma glucose and AHI (but not CT90) were the only variables independently associated with the mean adventitial VV density (R2 = 0.327). In conclusion, a high VV density is present in obese subjects with SAHS, and chronic intermittent hypoxia is pointed as an independent risk factor for the development of this early step of atheromatous disease.

| S-EPMC6363284 | biostudies-literature

Evaluation of coronary adventitial vasa vasorum using 3D optical coherence tomography--animal and human studies.

Project description:ObjectivesThis study sought to evaluate adventitial vasa vasorum (VV) in vivo with novel imaging technique of optical coherence tomography (OCT).MethodsTo verify OCT methods for quantification of VV, we first studied 2 swine carotid arteries in a model of focal angiogenesis by autologous blood injection, and compared microchannel volume (MCV) by OCT and VV by m-CT, and counts of those. In OCT images, adventitial MC was identified as signal-voiding areas which were located within 1 mm from the lumen-intima border. After manually tracing microchannel areas and the boundaries of lumen-intima and media-adventitial in all slices, we reconstructed 3D images. Moreover, we performed with OCT imaging in 8 recipients referred for evaluation of cardiac allograft vasculopathy at 1 year after heart transplantation. MCV and plaque volume (PV) were assessed with 3D images in each 10-mm-segment.ResultsIn the animal study, among the 16 corresponding 1-mm-segments, there were significant correlations of count and volume between both the modalities (count r(2) = 0.80, P < 0.01; volume r(2) = 0.50, P < 0.01) and a good agreement with a systemic bias toward underestimation with m-CT. In the human study, there was a significant positive correlation between MCV and PV (segment number = 24, r(2) = 0.63, P < 0.01).ConclusionOur results suggest that evaluation of MCV with 3D OCT imaging might be a novel method to estimate the amount of adventitial VV in vivo, and further has the potential to provide a pathophysiological insight into a role of the VV in allograft vasculopathy.

| S-EPMC4494669 | biostudies-literature

Vasa Vasorum Densities in Human Carotid Atherosclerosis Is Associated with Plaque Development and Vulnerability.

Project description:ObjectiveThe extensive vasa vasorum network functions as a conduit for the entry of inflammatory cells or factors that promote the progression of angiogenesis and plaque formation. Therefore, we investigated the correlation between the carotid vasa vasorum activities and carotid plaque vulnerability using indocyanine green video angiography (ICG-VA) during carotid endarterectomy (CEA).MethodsSixty-nine patients who underwent CEA were enrolled prospectively from September 2015 to December 2017. During CEA, a bolus of ICG was injected intravenously before and after resecting the atheroma. Additionally, we performed immunohistochemistry using CD68 (a surface marker of macrophages), CD117 (a surface marker of mast cells), and CD4 and CD8 (surface markers of T-cells) antibodies to analyze the resected plaque specimens.ResultsThe density of active vasa vasorum was observed in all patients using ICG-VA. The vasa vasorum externa (VVE) and interna (VVI) were seen in 11 (16%) and 57 patients (82.6%), respectively. Macroscopically, the VVE-type patterns were strongly associated with preoperative angiographic instability (81.8%, p=0.005) and carotid plaque vulnerability (90.9%, p=0.017). In contrast, the VVI-type patterns were weakly associated with angiographic instability (31.6%) and plaque vulnerability (49.1%). CD68-stained macrophages and CD117-stained mast cells were observed more frequently in unstable plaques than in stable plaques (p<0.0001, p=0.002, respectively).ConclusionThe early appearance of VVE, along with the presence of many microvessel channels that provided nutrients to the developing and expanding atheroma during ICG-VA, was strongly associated with unstable carotid plaques. The degree of infiltration of macrophages and mast cells is possibly related to the formation of unstable plaques.

| S-EPMC7054111 | biostudies-literature

Classification and Functional Characterization of Vasa Vasorum-Associated Perivascular Progenitor Cells in Human Aorta.

Project description:In the microcirculation, pericytes are believed to function as mesenchymal stromal cells (MSCs). We hypothesized that the vasa vasorum harbor progenitor cells within the adventitia of human aorta. Pericytes, endothelial progenitor cells, and other cell subpopulations were detected among freshly isolated adventitial cells using flow cytometry. Purified cultured pericytes were enriched for the MSC markers CD105 and CD73 and depleted of the endothelial markers von Willebrand factor and CD31. Cultured pericytes were capable of smooth muscle lineage progression including inducible expression of smooth muscle myosin heavy chain, calponin, and α-smooth muscle actin, and adopted a spindle shape. Pericytes formed spheroids when cultured on Matrigel substrates and peripherally localized with branching endothelial cells in vitro. Our results indicate that the vasa vasorum form a progenitor cell niche distinct from other previously described progenitor populations in human adventitia. These findings could have important implications for understanding the complex pathophysiology of human aortic disease.

| S-EPMC5511043 | biostudies-literature

Ginsenoside Rb1 Enhances Plaque Stability and Inhibits Adventitial Vasa Vasorum via the Modulation of miR-33 and PEDF.

Project description:Background: Atherosclerosis is closely associated with proliferation of the adventitial vasa vasorum, leading to the atherosclerotic plaque progression and vulnerability. In this report, we investigated the role of Ginsenoside Rb1 (Rb1) on atherosclerotic plaque stabilization and adventitial vasa vasorum (VV) along with the mechanisms involved. Methods and Results: Apolipoprotein E-deficient (ApoE-/-) mice were fed with a high-fat diet for 20 weeks, and then Ginsenoside Rb1 (50 mg/kg/d, intraperitoneal) was given for 4 weeks. Rb1 treatment significantly inhibited adventitial VV proliferation, alleviated inflammation, decreased plaque burden, and stabilized atherosclerotic plaques in apoE-/- mice. However, the beneficial effects of Rb1 on atherosclerotic lesion was attenuated by overexpression of miR-33. The analysis from atherosclerotic plaque revealed that Rb1 treatment could result in an induction of Pigment epithelium-derived factor (PEDF) expression and reduction of the miR-33 generation. Overexpression of miR-33 significantly reverted the Rb1-mediated elevation of PEDF and anti-angiogenic effect. Conclusions: Ginsenoside Rb1 attenuates plaque growth and enhances plaque stability partially through inhibiting adventitial vasa vasorum proliferation and inflammation in apoE-/- mice. The anti-angiogenic and anti-inflammation effects of Rb1 are exerted via the modulation of miR-33 and its target gene PEDF.

| S-EPMC8192703 | biostudies-literature

Coronary endothelial dysfunction is associated with inflammation and vasa vasorum proliferation in patients with early atherosclerosis.

Project description:ObjectiveEndothelial 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 resultsOptical 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).ConclusionsEpicardial 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.

| S-EPMC4212523 | biostudies-literature

Cell cycle and differentiation of Sca-1+ and Sca-1- hematopoietic stem and progenitor cells.

Project description:Hematopoietic stem and progenitor cells (HSPCs) are crucial for lifelong blood cell production. We analyzed the cell cycle and cell production rate in HSPCs in murine hematopoiesis. The labeling of DNA-synthesizing cells by two thymidine analogues, optimized for in-vivo use, enabled determination of the cell cycle flow rate into G2-phase, the duration of S-phase and the average cell cycle time in Sca-1+ and Sca-1- HSPCs. Determination of cells with 2n DNA content labeled in preceding S-phase was then used to establish the cell flow rates in G1-phase. Our measurements revealed a significant difference in how Sca-1+ and Sca-1- myeloid progenitors self-renew and differentiate. Division of the Sca-1+ progenitors led to loss of the Sca-1 marker in about half of newly produced cells, corresponding to asymmetric cell division. Sca-1- cells arising from cell division entered a new round of the cell cycle, corresponding to symmetric self-renewing cell division. The novel data also enabled the estimation of the cell production rates in Sca-1+ and in three subtypes of Sca-1- HSPCs and revealed Sca-1 negative cells as the major amplification stage in the blood cell development.

| S-EPMC6291262 | biostudies-literature

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