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- Al-Sharify, Dania, et al.
(författare)
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Increased proteolytic cleavage of osteoglycin is associated with a stable plaque phenotype and lower risk of cardiovascular events
- 2022
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 355, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Extracellular matrix (ECM) remodeling is one of the key components in the formation of vulnerable atherosclerotic plaques and cardiovascular events. We recently showed that the full-length ECM-proteoglycan osteoglycin was associated with plaque vulnerability and future cardiovascular events. In the present study, we aimed to investigate the association of cleaved osteoglycin with plaque phenotype. Methods: Two-hundred human carotid plaques were analyzed by immunohistochemistry. Cleaved osteoglycin and active caspase-3 were assessed by ELISA. ECM components (collagen, elastin and glycosaminoglycans) were assessed by colorimetric assays in plaque tissue homogenates. Matrix metalloproteinases (MMPs) were assessed using Milliplex. MMP-cleavage of osteoglycin and its effect on apoptosis were studied in vitro. Cardiovascular events were recorded during follow-up using national registries. Results: Plaque levels of cleaved osteoglycin were significantly higher in asymptomatic plaques and correlated to α-actin plaque area, collagen, elastin and inversely to lipids, active. caspase-3 and a histological vulnerability index. Cleaved osteoglycin correlated to several MMPs, especially MMP-12, which was also shown to cleave osteoglycin in vitro. In vitro cleavage of osteoglycin was also associated with less smooth muscle cell apoptosis. Patients with high plaque levels of cleaved osteoglycin had a significantly lower risk to suffer from future cardiovascular events. Conclusions: The current study shows that cleaved osteoglycin is associated with a stable plaque phenotype and lower risk for future cardiovascular events. Potentially due to reduced cell apoptosis and ability to retain LDL. These results indicate that targeting the cleavage of osteoglycin may be a potential therapeutic strategy to stabilize plaques.
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| 5. |
- Antza, C., et al.
(författare)
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Prevention of cardiovascular disease in young adults: Focus on gender differences. A collaborative review from the EAS Young Fellows
- 2023
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Ingår i: Atherosclerosis. - 0021-9150. ; 384
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Tidskriftsartikel (refereegranskat)abstract
- A steady rise in cardiovascular morbidity and mortality has been observed in young adults within the last decades. This trend corresponds to an increasing prevalence of traditional cardiovascular risk factors such as obesity and diabetes mellitus type 2 among young adults living in developed countries. Moreover, age-specific risk factors, such as substance abuse, contraceptive medication, and pregnancy-related diseases also correlate with an increased incidence of cardiovascular diseases. In this review, we discuss the available data for young adults on the epidemiology and the rationale for the causality of traditional and newly emerging risk factors of atherosclerotic cardiovascular diseases. We focus on gender-related differences in the exposure to these risk factors, investigate the recent data regarding screening and risk stratification in the young adult population, and describe the current state of the art on lifestyle and therapeutic intervention strategies in the primary prevention setting.
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- Assini, J. M., et al.
(författare)
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High levels of lipoprotein(a) in transgenic mice exacerbate atherosclerosis and promote vulnerable plaque features in a sex-specific manner
- 2023
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Ingår i: Atherosclerosis. - 0021-9150. ; 384
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Despite increased clinical interest in lipoprotein(a) (Lp(a)), many questions remain about the molecular mechanisms by which it contributes to atherosclerotic cardiovascular disease. Existing murine transgenic (Tg) Lp(a) models are limited by low plasma levels of Lp(a) and have not consistently shown a pro atherosclerotic effect of Lp(a). Methods: We generated Tg mice expressing both human apolipoprotein(a) (apo(a)) and human apoB-100, with pathogenic levels of plasma Lp(a) (range 87-250 mg/dL). Female and male Lp(a) Tg mice (Tg(LPA+/0;APOB+/0)) and human apoB-100-only controls (Tg(APOB+/0)) (n = 10-13/group) were fed a high-fat, high-cholesterol diet for 12 weeks, with Ldlr knocked down using an antisense oligonucleotide. FPLC was used to characterize plasma lipoprotein profiles. Plaque area and necrotic core size were quantified and immunohistochemical assessment of lesions using a variety of cellular and protein markers was performed. Results: Male and female Tg(LPA+/0;APOB+/0) and Tg(APOB+/0) mice exhibited proatherogenic lipoprotein profiles with increased cholesterol-rich VLDL and LDL-sized particles and no difference in plasma total cholesterol between genotypes. Complex lesions developed in the aortic sinus of all mice. Plaque area (+22%), necrotic core size (+25%), and calcified area (+65%) were all significantly increased in female Tg(LPA+/0;APOB+/0) mice compared to female Tg(APOB+/0) mice. Immunohistochemistry of lesions demonstrated that apo(a) deposited in a similar pattern as apoB-100 in Tg(LPA+/0;APOB+/0) mice. Furthermore, female Tg(LPA+/0;APOB+/0) mice exhibited less organized collagen deposition as well as 42% higher staining for oxidized phospholipids (OxPL) compared to female Tg(APOB+/0) mice. Tg(LPA+/0;APOB+/0) mice had dramatically higher levels of plasma OxPL-apo(a) and OxPL-apoB compared to Tg(APOB+/0) mice, and female Tg(LPA+/0;APOB+/0) mice had higher plasma levels of the proinflammatory cytokine MCP-1 (+3.1-fold) compared to female Tg(APOB+/0) mice. Conclusions: These data suggest a pro-inflammatory phenotype exhibited by female Tg mice expressing Lp(a) that appears to contribute to the development of more severe lesions with greater vulnerable features.
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- Bergström, Göran, 1964, et al.
(författare)
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Body weight at age 20 and in midlife is more important than weight gain for coronary atherosclerosis: Results from SCAPIS.
- 2023
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 373, s. 46-54
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Tidskriftsartikel (refereegranskat)abstract
- Elevated body weight in adolescence is associated with early cardiovascular disease, but whether this association is traceable to weight in early adulthood, weight in midlife or to weight gain is not known. The aim of this study is to assess the risk of midlife coronary atherosclerosis being associated with body weight at age 20, body weight in midlife and body weight change.We used data from 25,181 participants with no previous myocardial infarction or cardiac procedure in the Swedish CArdioPulmonary bioImage Study (SCAPIS, mean age 57 years, 51% women). Data on coronary atherosclerosis, self-reported body weight at age 20 and measured midlife weight were recorded together with potential confounders and mediators. Coronary atherosclerosis was assessed using coronary computed tomography angiography (CCTA) and expressed as segment involvement score (SIS).The probability of having coronary atherosclerosis was markedly higher with increasing weight at age 20 and with mid-life weight (p<0.001 for both sexes). However, weight increase from age 20 until mid-life was only modestly associated with coronary atherosclerosis. The association between weight gain and coronary atherosclerosis was mainly seen in men. However, no significant sex difference could be detected when adjusting for the 10-year delay in disease development in women.Similar in men and women, weight at age 20 and weight in midlife are strongly related to coronary atherosclerosis while weight increase from age 20 until midlife is only modestly related to coronary atherosclerosis.
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| 14. |
- Bjerre, Mette, et al.
(författare)
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Serum osteoprotegerin as a long-term predictor for patients with stable coronary artery disease and its association with diabetes and statin treatment : A CLARICOR trial 10-year follow-up substudy
- 2020
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 301, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Elevated circulating levels of osteoprotegerin (OPG) are known to add to the prediction of cardiovascular mortality. Our objective was to clarify the long-term risk associated with serum OPG and the possible influence of diabetes and statins on OPG levels in patients with stable coronary artery disease (CAD).METHODS: We assessed the placebo-treated group (n = 1998) from the CLARICOR trial (NCT00121550), a cohort with stable CAD. At entry, 15% of the participants had diabetes and 41% received statins. Serum OPG levels were measured in blood drawn at randomization. Participants were followed through public registers for 10 years.RESULTS: OPG levels correlated positively with diabetes status, age, CRP and female sex, but negatively with the use of statins. CAD participants with diabetes had significantly elevated serum OPG levels compared to participants without diabetes, p < 0.0001. The participants without diabetes treated with statins presented with significantly lower serum OPG levels than the corresponding non-statin-users (p < 0.0001). However, statin use showed no association with OPG levels in the participants with diabetes. High OPG levels at entry showed long-term associations with all-cause mortality and cardiovascular events (hazard ratio associated with factor 10 OPG increase 15.9 (95% CI 11.0-22.9) and 6.38 (4.60-8.90), p = 0.0001, even after adjustment for standard predictors (3.16 (1.90-5.25) and 2.29 (1.53-3.44), p < 0.0001).CONCLUSIONS: Circulating OPG holds long-term independent predictive ability for all-cause mortality and cardiovascular events in CAD participants. OPG levels were associated with diabetes, age, and female sex and statin treatment was associated with lower OPG levels in the absence of diabetes.
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| 15. |
- Björnson, Elias, 1988, et al.
(författare)
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The relationship between genetic liver fat and coronary heart disease is explained by apoB-containing lipoproteins
- 2024
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Ingår i: ATHEROSCLEROSIS. - 0021-9150 .- 1879-1484. ; 388
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relationship between genetically -driven liver fat and coronary heart disease (CHD) remains unclear. ApoB-containing lipoproteins are known causal factors for CHD and may explain this relationship. Methods and Results: We conducted a genome-wide association study (GWAS) in the UK Biobank to identify genetic variants associated with liver fat. We then investigated the effects that these genetic variants had on both apoB-containing lipoproteins and CHD. Using Mendelian Randomization (MR) analyses, we examined if the relationship between genetically -driven liver fat and CHD could be attributed to its effect on apoB-containing lipoproteins. We found 25 independent liver -fat associated single -nucleotide polymorphisms (SNPs) with differing effects on lipoprotein metabolism. The SNPs were classified into three groups/clusters. The first cluster (N = 3 SNPs) displayed lipoprotein -raising effects. The second cluster (N = 12 SNPs) displayed neutral effects on lipoproteins and the third cluster (N = 10 SNPs) displayed lipoprotein -lowering effects. For every 1% higher liver fat, the first cluster showed an increased risk of CHD (OR = 1.157 [95% CI: 1.108-1.208]). The second cluster showed a non -significant effect on CHD (OR = 0.988 [95% CI: 0.965-1.012], whereas the third cluster showed a protective effect of increased liver fat on CHD (OR = 0.942 [95% CI: 0.897-0.989]). When adjusting for apoB, the risk for CHD became null. Conclusions: Here, we identify 25 liver -fat associated SNPs. We find that SNPs that increase, decrease or have neutral effects on apoB-containing lipoproteins show increased, decreased or neutral effects on CHD, respectively. Therefore, the relationship between genetically -driven liver fat and CHD is mediated by the causal effect of apoB.
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| 18. |
- Catapano, Alberico L, et al.
(författare)
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Evaluation of lipoprotein(a) in the prevention and management of atherosclerotic cardiovascular disease: A survey among the Lipid Clinics Network
- 2023
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 370, s. 5-11
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: The European Atherosclerosis Society (EAS) Lipid Clinics Network promoted a survey in order to identify and understand how and when lipoprotein(a) [Lp(a)] is tested and clinically evaluated in lipid clinics throughout Europe, and the challenges that may prevent evaluation from being carried out. Methods: This survey was divided into three areas of inquiry: background and clinical setting information of clinicians, questions for doctors who claimed not to measure Lp(a), in order to understand what were the reasons for not ordering the test, and questions for doctors who measure Lp(a), to investigate the use of this value in the management of patients. Results: A total of 151 centres clinicians filled in the survey, out of 226 invited. The proportion of clinicians who declare to routinely measure Lp(a) in clinical practice was 75.5%. The most common reasons for not ordering the Lp(a) test were the lack of reimbursement or of treatment options, the non-availability of Lp(a) test, and the high cost of performing the laboratory test. The availability of therapies targeting this lipoprotein would result in a greater propensity of clinicians to start testing Lp(a). Among those who declared to routinely measure Lp(a), the Lp(a) measurement is mostly requested to further stratify patients’ cardiovascular risk, and half of them recognized 50 mg/dL (approx. 110 nmol/L) as the threshold for increased cardiovascular risk due. Conclusions: These results warrant for a great deal of effort from scientific societies to address the barriers that limit the routine use of the measurement of Lp(a) concentration and to recognise the importance of Lp(a) as a risk factor.
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- Genovese, Federica, et al.
(författare)
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Plasma levels of PRO-C3, a type III collagen synthesis marker, are associated with arterial stiffness and increased risk of cardiovascular death
- 2024
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Ingår i: Atherosclerosis. - 0021-9150. ; 388
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: The N-terminal propeptide of type III collagen (PRO-C3) assay measures a pro-peptide released during type III collagen synthesis, an important feature of arterial stiffening and atherogenesis. There is a clinical need for improved non-invasive, cheap and easily accessible methods for evaluating individuals at risk of cardiovascular disease (CVD). In this study, we investigate the potential of using circulating levels of PRO-C3 to mark the degree of vascular stenosis and risk of cardiovascular events. Methods: Baseline plasma levels of PRO-C3 were measured by ELISA in subjects belonging to the SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort (N = 1354). Associations between PRO-C3 levels with vascular characteristics, namely stiffness and stenosis, and risk of future cardiovascular events were explored. Subjects were followed up after a median of 35 months (interquartile range 34–36 months), with recorded outcomes cardiovascular death and all-cause mortality. Results: We found a correlation between PRO-C3 levels and pulse wave velocity (rho 0.13, p = 0.000009), a measurement of arterial stiffness. Higher PRO-C3 levels were also associated with elevated blood pressure (rho 0.07, p = 0.014), as well as risk of cardiovascular mortality over a three-year follow-up period (OR 1.56, confidence interval 1.008–2.43, p = 0.046). Conclusions: Elevated circulating PRO-C3 levels are associated with arterial stiffness and future cardiovascular death, in the SUMMIT cohort, suggesting a potential value of PRO-C3 as a novel marker for declining vascular health.
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| 40. |
- Hayderi, Assim, 1990-, et al.
(författare)
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Function of viperin in human aortic SMCS and its relevance for atherosclerosis
- 2021
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 331, s. E88-E88
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: During atherosclerosis, activated vascular cells secrete chemokines to recruit leukocytes to the subendothelial space. Activated leukocytes, in particular activated T lymphocytes express IFN-γ, which affects the expression of numerous genes, including the antiviral protein viperin, in vascular cells. Viperin is expressed in endothelial cells of human carotid plaques but its relevance for vascular physiology and/or pathophysiology has not been established (Olofsson et al., 2005). We aimed at studying the function of viperin in human AoSMCs.Methods: Immunostaining of human carotid plaques was performed to determine the expression and localization of viperin in carotid plaques. To study the role of viperin in regulation of vascular inflammation, viperin was silenced using siRNA in cultured human AoSMCs, prior to stimulation with IFN-γ. Release of inflammatory mediators was analyzed using OLINK proteomics and ELISA, and the gene expression was analyzed by qRT-PCR.Results: Viperin is expressed in endothelial cells, macrophages and smooth muscle cells in human carotid plaques. OLINK data analysis revealed reduction in release of CCL3, CXCL9, CXCL10 and CXCL11 by AoSMCs that were targeted with anti-viperin siRNA prior to stimulation with IFN-γ. Using ELISA and qRT-PCR, we could confirm the reduction of IFN-γ-induced CXCL10 and CXCL11 in viperin knockdown AoSMCs.Conclusions: Viperin is expressed in human carotid plaques and seem to be involved in regulating the expression of CXCL10 and CXCL11 in AoSMCs. Thus, it may play a role in recruitment of T lymphocytes to the subendothelial space in atherosclerotic plaques.
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| 41. |
- Hayderi, A., 1990-, et al.
(författare)
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Interferon gamma reprograms glutamine metabolic pathways in human aortic smooth muscle cells
- 2023
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 379:Suppl. 1, s. S8-S8
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: Cells within atherosclerotic lesions have a higher glutamine demand than cells in healthy vessel although glutaminase, the enzyme converting glutamine to glutamate, is significantly downregulated in human carotid lesions. This may suggest rewiring of glutamine metabolic pathways in atherosclerotic lesions, caused by infiltrating immune cells and or their cytokines. Here we aimed at exploring the enzymes and transporters involved in glutamine metabolism in human carotid atherosclerotic tissues and aortic smooth muscle cells (hAoSMCs) exposed to interferon gamma.Methods: Protein and mRNA from interferon gamma-treated hAoSMCs were subjected to Western blot or qRT-PCR for quantification of enzymes and transporters involved in glutamine metabolism. H2DCFDA probe was utilized for detection of intracellular reactive oxygen species (ROS) using flow cytometry. The expression of these enzymes and transporters was also evaluated in human carotid lesions (GEO accession: GSE43292).Results: Interferon-treated hAoSMCs display a significantly lower expression of glutaminase followed by an increase in the expression of glutamine transporters, glutamine synthetase and glutamine-fructose-6-phosphate transaminase-1 (GFPT1). The level of ROS and the expression of enzymes involved in de novo synthesis of glutathione are elevated in interferon-treated cells. A similar expression pattern for these genes, expect for GFPT1, is also evident in human carotid lesions where glutaminase mRNA shows a strong positive correlation with SMC markers and a strong negative correlation with macrophage markers.Conclusions: Glutamine metabolism is disrupted in human carotid lesions and interferon gamma alters glutamine metabolism in hAoSMCs, which may favor the production of UDP-GlcNAc and reactive oxygen species.
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| 42. |
- Hlebowicz, Joanna, et al.
(författare)
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Carotid atherosclerosis, changes in tissue remodeling and repair in patients with aortic coarctation
- 2021
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 335, s. 47-52
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: After aortic coarctation (CoA) repair, patients still suffer from cardiovascular complications. The aim of this study was to measure cardiovascular markers, intima-media thickness (IMT) and plaques in controls and patients with CoA. Methods: Sixty-four patients with CoA (66% male, mean age 48 ± 15 years) and controls (54% men, mean age 47 ± 16 years) underwent ultrasound of their arteries. A multiplex platform to analyze circulating blood levels biomarkers reflecting inflammation, tissue remodeling and repair was used. Results: In men following CoA repair, a significantly increased carotid bulb IMT was observed in comparison to the control group (1.05 [0.72–1.24] vs. 0.67 [0.59–0.95] mm; p = 0.003). Median common carotid artery (CCA) IMT was increased in men compared to controls (0.82 [0.61–0.97] mm vs. 0.58 [0.53–0.76] mm, p < 0.003) and in women compared to controls (0.83 [0.70–0.92] vs. 0.60 [0.55–0.69], p < 0.004). CoA demonstrated an independent association with IMT in both men and women. Men with CoA were also more likely to have a plaque in their carotid arteries (p = 0.010). In women with CoA, we observed significantly lower levels of stem cell factor (SCF, p = 0.004) while in men with CoA we observed significantly lower levels of matrix metalloproteinase-3 (MMP-3, p = 0.048), tumor necrosis factor receptor 1 (TNF-R1, p = 0.032), tumor necrosis factor receptor superfamily member 10B (TRAIL-R2, p = 0.019) and monocyte chemotactic protein 1 (MCP-1, p = 0.015). Conclusions: This is the first study to show that despite successful CoA repair, patients have more carotid atherosclerosis than can be explained by changes in tissue remodeling and repair.
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| 48. |
- Katra, Pernilla, et al.
(författare)
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Plasma levels of CCL21, but not CCL19, independently predict future coronary events in a prospective population-based cohort
- 2023
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 366, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: The homeostatic chemokines CCL21 and CCL19 have been explored as biomarkers in cardiovascular disease prediction in patients with established cardiovascular disease, but associations between these chemokines and first-time coronary event incidence have not been investigated before. Here, we explored associations between CCL21 or CCL19 and first-time incident coronary events in the general population-based Malmö Diet and Cancer cohort with two decades of follow-up.METHODS: CCL21 and CCL19 levels in plasma were analysed with ELISA and proximity extension assay and associations with disease incidence were explored with conditional logistic regression in a nested case-control cohort (CCL21; n = 676) and with Cox regression in a population-based cohort (CCL19; n = 4636).RESULTS: High CCL21 levels in plasma were associated with incident first-time coronary events independently of traditional risk factors (odds ratio of 2.64 with 95% confidence interval 1.62-4.31, p < 0.001, comparing the highest versus the lowest tertile of CCL21), whereas CCL19 was not. CCL19 was, however, associated with incident heart failure, as well as increased all-cause, cardiovascular and cancer mortality independently of age and sex.CONCLUSIONS: Even though CCL21 and CCL19 both signal through CCR7, these chemokines may not be interchangeable as disease predictors and CCL21 could be used for prediction of future coronary events in individuals without any previous coronary heart disease history.
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| 49. |
- Kilbo Edlund, Karl, et al.
(författare)
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Long-term ambient air pollution and coronary atherosclerosis : results from the Swedish SCAPIS study
- 2024
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484.
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Despite firm evidence for an association between long-term ambient air pollution exposure and cardiovascular morbidity and mortality, results from epidemiological studies on the association between air pollution exposure and atherosclerosis have not been consistent. We investigated associations between long-term low-level air pollution exposure and coronary atherosclerosis.Methods: We performed a cross-sectional analysis in the large Swedish CArdioPulmonary bioImaging Study (SCAPIS, n = 30 154), a random general population sample. Concentrations of total and locally emitted particulate matter <2.5 μm (PM2.5), <10 μm (PM10), and nitrogen oxides (NOx) at the residential address were modelled using high-resolution dispersion models. We estimated associations between air pollution exposures and segment involvement score (SIS), coronary artery calcification score (CACS), number of non-calcified plaques (NCP), and number of significant stenoses, using ordinal regression models extensively adjusted for potential confounders.Results: Median 10-year average PM2.5 exposure was 6.2 μg/m3 (range 3.5–13.4 μg/m3). 51 % of participants were women and 51 % were never-smokers. None of the assessed pollutants were associated with a higher SIS or CACS. Exposure to PM2.5 was associated with NCP (adjusted OR 1.34, 95 % CI 1.13, 1.58, per 2.05 μg/m3). Associations with significant stenoses were inconsistent.Conclusions: In this large, middle-aged general population sample with low exposure levels, air pollution was not associated with measures of total burden of coronary atherosclerosis. However, PM2.5 appeared to be associated with a higher prevalence of non-calcified plaques. The results suggest that increased risk of early-stage atherosclerosis or rupture, but not increased total atherosclerotic burden, may be a pathway for long-term air pollution effects on cardiovascular disease.
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| 50. |
- Kluza, Ewelina, et al.
(författare)
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Diverse ultrastructural landscape of atherosclerotic endothelium
- 2021
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 339, s. 35-45
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: The endothelium plays a major role in atherosclerosis, yet the endothelial plaque surface is a largely uncharted territory. Here we hypothesize that atherosclerosis-driven remodeling of the endothelium is a dynamic process, involving both damaging and regenerative mechanisms. Methods: Using scanning electron microscopy (SEM) and immuno-SEM, we studied endothelial junction ultrastructure, endothelial openings and immune cell-endothelium interactions in eight apoe−/− mice and two human carotid plaques. Results: The surface of early mouse plaques (n = 11) displayed a broad range of morphological alterations, including junctional disruptions and large transcellular endothelial pores with the average diameter between 0.6 and 3 μm. The shoulder region of advanced atherosclerotic lesions (n = 7) had a more aggravated morphology with 8 μm-size paracellular openings at two-fold higher density. In contrast, the central apical surface of advanced plaques, i.e., the plaque body (n = 7), displayed endothelial normalization, as shown by a significantly higher frequency of intact endothelial junctions and a lower incidence of paracellular pores. This normalized endothelial phenotype correlated with low immune cell density (only 5 cells/mm2). The human carotid plaque surface (n = 2) displayed both well-organized and disrupted endothelium with similar features as described above. In addition, they were accompanied by extensive thrombotic areas. Conclusions: Our study unveils the spectrum of endothelial abnormalities associated with the development of atherosclerosis. These were highly abundant in early lesions and in the shoulder region of advanced plaques, while normalized at the advanced plaque's body. Similar endothelial features were observed in human atherosclerotic plaques, underlining the versatility of endothelial transformations in atherosclerosis.
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