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Aims/hypothesis Diabetes is associated with an increased risk of cancer. Prostasin is an epithelial sodium channel stimulator that has been associated with suppression of tumours, glucose metabolism and hyperglycaemia-associated tumour pathology. However, the association between prostasin, diabetes and cancer mortality has not been well investigated in humans. We aim to investigate the associations between plasma prostasin and diabetes, and to explore whether prostasin has an effect on cancer mortality risk in individuals with hyperglycaemia. Methods Plasma prostasin was measured using samples from the Malmö Diet and Cancer Study Cardiovascular Cohort, and statistical analysis was performed from both sex-specific quartiles and per 1 SD. The cross-sectional association between plasma prostasin and diabetes was first studied in 4658 participants (age 57.5 ± 5.9 years, 39.9% men). After excluding 361 with prevalent diabetes, the associations of prostasin with incident diabetes and cancer mortality risk were assessed using Cox regression analysis. The interactions between prostasin and blood glucose levels as well as other covariates were tested. Results The adjusted OR for prevalent diabetes in the 4th vs 1st quartile of prostasin concentrations was 1.95 (95% CI 1.39, 2.76) (p for trend p for trend p for interaction =0.022), with a stronger association observed in individuals with impaired fasting blood glucose levels at baseline (HR per 1 SD change 1.52; 95% CI 1.07, 2.16; p=0.019). Conclusions/interpretation Plasma prostasin levels are positively associated with diabetes risk and with cancer mortality risk, especially in individuals with high blood glucose levels, which may shed new light on the relationship between diabetes and cancer. Graphical abstract

As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18–71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms. Electronic supplementary material The online version of this article (10.1007/s10654-020-00695-4) contains supplementary material, which is available to authorized users.

Atherosclerotic plaques are characterized by an accumulation and subsequent oxidation of LDL, resulting in adaptive immune responses against formed or exposed neoepitopes of the LDL particle. Autoantibodies against native p210, the 3136–3155 amino acid sequence of the LDL protein apolipoprotein B-100 (apoB100) are common in humans and have been associated with less severe atherosclerosis and decreased risk for cardiovascular events in clinical studies. However, whether apoB100 native p210 autoantibodies play a functional role in atherosclerosis is not known. In the present study we immunized apoE-/- mice with p210-PADRE peptide to induce an antibody response against native p210. We also injected mice with murine monoclonal IgG against native p210. Control groups were immunized with PADRE peptide alone or with control murine monoclonal IgG. Immunization with p210-PADRE induced an IgG1 antibody response against p210 that was associated with reduced atherosclerotic plaque formation in the aorta and reduced MDA-LDL content in the lesions. Treatment with monoclonal p210 IgG produced a similar reduction in atherosclerosis as immunization with p210-PADRE. Our findings support an atheroprotective role of antibodies against the apoB100 native p210 and suggest that vaccines that induce the expression of native p210 IgG represent a potential therapeutic strategy for lowering cardiovascular risk.

Novel methods to characterize the plasma proteome has made it possible to examine a wide range of proteins in large longitudinal cohort studies, but the complexity of the human proteome makes it difficult to identify robust protein-disease associations. Nevertheless, identification of individuals at high risk of early mortality is a central issue in clinical decision making and novel biomarkers may be useful to improve risk stratification. With adjustment for established risk factors, we examined the associations between 138 plasma proteins measured using two proximity extension assays and long-term risk of all-cause mortality in 3,918 participants of the population-based Malmö Diet and Cancer Study. To examine the reproducibility of protein-mortality associations we used a two-step random-split approach to simulate a discovery and replication cohort and conducted analyses using four different methods: Cox regression, stepwise Cox regression, Lasso-Cox regression, and random survival forest (RSF). In the total study population, we identified eight proteins that associated with all-cause mortality after adjustment for established risk factors and with Bonferroni correction for multiple testing. In the two-step analyses, the number of proteins selected for model inclusion in both random samples ranged from 6 to 21 depending on the method used. However, only three proteins were consistently included in both samples across all four methods (growth/differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide, and epididymal secretory protein E4). Using the total study population, the C-statistic for a model including established risk factors was 0.7222 and increased to 0.7284 with inclusion of the most predictive protein (GDF-15; P

Macrophages are a functionally heterogeneous group of immune cells abundant in atherosclerotic plaques. Macrophages expressing CD163 are associated with intraplaque hemorrhage and have previously been considered atheroprotective. However, in a recent study CD163-deficient atherosclerotic ApoE−/− mice exhibited smaller and less complex plaques, suggesting a proatherogenic role of CD163. Previous smaller studies on CD163+ macrophages and plaque stability in humans have yielded diverging results. Here we assessed the association of CD163+ cells to plaque vulnerability in a large cohort of human carotid plaques. CD163 protein expression was analyzed by immunohistochemistry in 200 human carotid plaques removed by endarterectomy from 103 patients with and 93 patients without cerebrovascular symptoms. Furthermore, CD163 mRNA expression was analyzed in 66 of the plaques. Both protein and mRNA expression of CD163 was higher in plaques from symptomatic patients and in plaques with high vulnerability index. CD163+ macrophages were primarily found in shoulder regions and in the center of the plaques. The present data show that CD163 is associated with increased plaque vulnerability in human carotid plaques, supporting the notion that CD163+ macrophages could contribute to clinical events.

Aims/hypothesis Growth differentiation factor 15 (GDF-15) is an anti-inflammatory cytokine of the transforming growth factor-β superfamily. Circulating levels of GDF-15 are associated with hyperglycaemia among people with obesity or diabetes, but longitudinal evidence on the association between GDF-15 levels and diabetes risk is scarce. Our aim was to explore whether circulating levels of GDF-15 at baseline are positively associated with future diabetes incidence in a middle-aged urban population. Methods Between 1991 and 1994, baseline fasting plasma GDF-15 levels were measured in 4360 individuals without diabetes (mean age 57.4 ± 5.96 years, 38.6% men) who were participants in the Malmö Diet and Cancer–Cardiovascular Cohort. After a follow-up of 19.0 ± 5.16 years (mean ± SD), Cox proportional hazards regression analysis was used for the study of the relationship between baseline GDF-15 and incident diabetes, with adjustment for established confounders. A sensitivity analysis included further adjustment for levels of C-reactive protein (CRP). Results During the follow-up period, 621 individuals developed diabetes. The multivariate-adjusted HR for diabetes incidence was 1.43 (95% CI 1.11, 1.83; p for trend = 0.007) for the fourth compared with the first quartile of GDF-15, and was 1.17 (95% CI 1.07, 1.28; p 55 and ≤60) and >60 years, respectively. With adjustment for levels of CRP, the HR per SD increase of GDF-15 (1.21, 95% CI 1.09, 1.35) was significant (p = 0.015), but the HR for the fourth compared with the first quartile of GDF-15 was not significant (HR 1.30; 95% CI 1.01, 1.67; p for trend = 0.061). Conclusions/interpretation GDF-15 may be useful for identification of people with a risk of incident diabetes, especially if those people are ≤60 years old.

The notion that atherosclerosis can be prevented or mitigated by vaccination is now moving towards clinical trials. This strategy is based on the existence of autoimmunity to LDL, the cholesterol-carrying particles that accumulate in arteries. In this Comment, we discuss the underlying concepts, research basis and challenges for the development of a vaccine against atherosclerosis.

Background Though subjective, poor self-rated health (SRH) has consistently been shown to predict cardiovascular disease (CVD). The underlying mechanism is unclear. This study evaluates the associations of SRH with biomarkers for CVD, aiming to explore potential pathways between poor SRH and CVD. Methods Based on the Malmö Diet and Cancer Cardiovascular Cohort study, a targeted proteomics approach was used to assess the associations of SRH with 88 cardiovascular risk proteins, measured in plasma from 4521 participants without CVD. The false discovery rate (FDR) was controlled using the Benjamini and Hochberg method. Covariates taken into consideration were age, sex, traditional CVD risk factors (low-density lipoprotein cholesterol, systolic blood pressure, anti-hypertensive medication, diabetes, body mass index, smoking), comorbidity, life-style and psycho-social factors (education level, living alone, alcohol consumption, low physical activity, psychiatric medication, sleep duration, and unemployment). Results Age and sex-adjusted associations with SRH was found for 34 plasma proteins. Nine of them remained significant after adjustments for traditional CVD risk factors. After further adjustment for comorbidity, life-style and psycho-social factors, only leptin (β = − 0.035, corrected p = 0.016) and C–C motif chemokine 20 (CCL20; β = − 0.054, corrected p = 0.016) were significantly associated with SRH. Conclusions Poor SRH was associated with raised concentrations of many plasma proteins. However, the relationships were largely attenuated by adjustments for CVD risk factors, comorbidity and psycho-social factors. Leptin and CCL20 were associated with poor SRH in the present study and could potentially be involved in the SRH–CVD link.

The genetic structure of nine wild, seven hatchery-reared, and one presumably mixed, sea trout (Salmo trutta L.) populations sampled from watersheds along the Swedish Baltic Sea coast was analysed using ten microsatellite loci. DNA-information was evaluated as a baseline for mixed stock analysis (MSA) and individual assignment (IA). A clear genetic structure with distinct populations was identified (global F ST = 0.066), with significant regional differentiation. Average gene diversity (H e) was similar among samples of wild and reared trout, whereas levels of heterozygote deficiency differed significantly (wild: H e = 0.70, F IS = 0.075; reared: H e = 0.69, F IS = 0.022). The high F IS found in wild samples indicates presence of within-river sub-structuring. Evaluation with realistic-fishery simulations indicated that the baseline resolution was sufficient for MSA, at least at a regional level. Hierarchical MSA and IA analyses of real catches from two coastal fisheries showed that populations from the northern region contributed about 90 % to the catch. Analysed individually, the two fisheries differed in catch compositions despite a short geographic distance among sites. One fishery mainly caught sea trout from a small wild population whereas the other fishery was dominated by reared sea trout. Stock composition analysis is a valuable tool for refining exploitation rate estimates for individual sea trout populations in mixed coastal fisheries, as well as for investigating migration patterns in the Baltic Sea.

Background Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. Methods Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). Results Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. Conclusions Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.

Androgen-deprivation therapy (ADT) for prostate cancer has been associated with increased risk for development of cardiovascular events and recent pooled analyses of randomized intervention trials suggest that this primarily is the case for patients with pre-existing cardiovascular disease treated with gonadotropin-releasing hormone receptor (GnRH-R) agonists. In the present study we investigated the effects of the GnRH-R agonist leuprolide and the GnRH-R antagonist degarelix on established atherosclerotic plaques in ApoE−/− mice. A shear stress modifier was used to produce both advanced and more stable plaques in the carotid artery. After 4 weeks of ADT, increased areas of necrosis was observed in stable plaques from leuprolide-treated mice (median and IQR plaque necrotic area in control, degarelix and leuprolide-treated mice were 0.6% (IQR 0–3.1), 0.2% (IQR 0–4.4) and 11.0% (IQR 1.0-19.8), respectively). There was also evidence of increased inflammation as assessed by macrophage immunohistochemistry in the plaques from leuprolide-treated mice, but we found no evidence of such changes in plaques from control mice or mice treated with degarelix. Necrosis destabilizes plaques and increases the risk for rupture and development of acute cardiovascular events. Destabilization of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH-R agonists.

Telemetric and molecular techniques are powerful tools for investigating patterns of species dispersal, habitat use, and reproductive behavior. Yet, these methods are rarely combined when studying spatial structures of migrating animals. This study combines migration data with genetic assignment tests of radio-tagged sea trout, Salmo trutta L., in two Swedish rivers. We investigate how the genetic information enhances the interpretation of the telemetry data. Individual gene frequencies of tagged fish are assigned to baseline samples of brown trout collected in tributaries and the main stems. The genetic assignment tests confirm that individuals returned from the sea to their natal stream, but also suggest that some individuals migrated to other than their native habitat. In total, 82% (R. Pitealven) and 37% (R. Vindelalven) of fish that were successfully assigned to a sample in a baseline migrated to an area in the vicinity of the sample location. The difference between rivers is likely due to low genetic differentiation among baseline samples and effects of stocking of fish in the R. Vindelalven. Combining the two techniques enhances understanding of migration behavior, important for conservation and management.

We present an overview of 27 years of experience of domestication and farming of Arctic charr (Salvelinus alpinus) in Sweden. The domestication process included an evaluation of suitable strains for farming, a breeding programme and the study of the biological and behavioural characteristics of the species. Traits of three different Arctic charr populations differing in ecology and appearance were compared during initial 2-year trials under farming conditions. The best-performing population with respect to the growth rate and the lowest frequency of early sexual maturation was a piscivore form and this became the foundation for a breeding programme intended to select for an Arctic charr strain suitable for farming. After 23 years and 7 generations, our selective breeding has resulted in a fast-growing, late-maturing strain much appreciated by farmers. The biological and behavioural characteristics studied included annual and diel locomotor activity, feeding, social and thermal behaviour. Applying our findings in these areas has greatly improved both profits and conditions for the fish. Other investigations have focused on the application and further evaluation of the results from research in practical farming trials, such as evaluation of growth at different farms with different temperature conditions, optimal time and stocking density for start-feeding and evaluation of different feeding schedules. In Sweden, Arctic charr is mainly farmed in net pens situated in nutritionally depleted and extremely unproductive water reservoirs formed by damming rivers to create electric power. Judicious farming of Arctic charr in such reservoirs can restore their nutritional and productivity state to that which existed before regulation. Site selection criteria for Arctic charr farming in such waters have been developed. The development of intensive farming of Arctic charr in Sweden is discussed together with current limitations and future possibilities.

Atherosclerosis involves the formation of inflammatory arterial lesions and is one of the most common causes of death globally. It has been evident for more than 20 years that adaptive immunity regulates the magnitude of the atherogenic proinflammatory response. T cells may also influence the stability of the atherosclerotic lesion and thus the propensity for thrombus formation and the clinical outcome of disease. Immunization of hypercholesterolemic animals with low-density lipoprotein preparations reduces atherosclerosis, suggesting that vaccination may represent a useful strategy for disease prevention or modulation. This review summarizes our current understanding of the role immunity in atherosclerosis and outlines strategies for antigen-specific prevention of this disease.

Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy. We have previously shown injury-induced neointima formation of the carotid artery in mice with the mdx mutation (causing dystrophin deficiency) to be increased. To investigate the role of dystrophin in intimal recruitment of smooth muscle cells (SMCs) that maintains plaque stability in atherosclerosis we applied a shear stress-modifying cast around the carotid artery of apolipoprotein E (ApoE)-null mice with and without the mdx mutation. The cast induces formation of atherosclerotic plaques of inflammatory and SMC-rich/fibrous phenotypes in regions of low and oscillatory shear stress, respectively. Unexpectedly, presence of the mdx mutation markedly reduced the development of the inflammatory low shear stress plaques. Further characterization of the low shear stress plaques in ApoE-null mdx mice demonstrated reduced infiltration of CD3+ T cells, less laminin and a higher SMC content. ApoE-null mdx mice were also found to have a reduced fraction of CD3+ T cells in the spleen and lower levels of cytokines and monocytes in the circulation. The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.

Patterns of genetic diversity and differentiation among five wild and four hatchery populations of Atlantic salmon in the Baltic Sea were assessed based on eight assumedly neutral microsatellite loci and six gene-associated markers, including four expressed sequence tag (EST) linked and two major histocompatibility complex (MHC) linked tandem repeat markers (micro- and mini-satellites). The coalescent simulations based on the method of Beaumont and Nichols (1996, Proc. R. Soc. Lond. Ser. B – Biol. Sci., 263, 1619–1626) indicated that two loci (MHCIIα and Ssa171, with the lowest and highest overall FST estimates, respectively) exhibited significant departures (P

Background: Central haemodynamic parameters derived from reservoir pressure analysis (RPA-parameters) exhibit prognostic utility. Alterations in reservoir function could have an unfavourable influence on target organs, such as the kidneys. We determined in older adults whether these RPA-parameters would be associated with the reduction in estimated glomerular filtration rate (eGFR) during a 3-year follow-up period. Methods: We studied 544 individuals (69.4 ± 7.9 yrs, 195F, 235CVD) at baseline and after 3 years. RPA-parameters including reservoir pressure integral (INTPR), peak reservoir pressure, excess pressure integral, systolic and diastolic rate constants were obtained by radial artery tonometry. Results: After 3 years, 95 individuals (72.4 ± 7.6 yrs, 26F) had an eGFR reduction of more than 5 ml/min/1.73 m2/year. A multivariate logistic regression analysis revealed that baseline INTPR was independently associated with the eGFR reduction after adjusting for conventional risk factors and baseline renal function [odds ratio 0.975 (95% CI, 0.958–0.993), p < 0.01]. When the eGFR reduction was expressed as a continuous variable, baseline INTPR was also independently associated with changes in eGFR (β = 0.115, p < 0.01; multivariate linear regression with adjustment for conventional risk factors and baseline renal function). These associations remained unchanged after further adjustments for central artery stiffness or traditional central haemodynamic parameters. No other RPA-parameters exhibited significant associations. Conclusions: These findings demonstrate that baseline INTPR is independently associated with the eGFR reduction in older adults, suggesting that INTPR may play a role in the functional decline of the kidneys.

For many centuries, human activities have become progressively more significant forces in the biogeochemical circulation of matter in the earth. In recent decades, the phenomena and effects of acidification have played a central role in scientific and social learning about both human impacts on ecosystems and the importance of regional, international, and global strategies in environmental protection.

Background Macrophage foam cell formation is a prominent feature of human atherosclerotic plaques, usually considered to be correlated to uptake of and inflammatory response to oxidized low density lipoproteins (OxLDL). However, there are alternative pathways for formation of macrophage foam cells and the effect of such lipid loading on macrophage function remains to be fully characterized. In the present study we investigated basal and inducible cytokine expression in primary human macrophages either loaded with triglycerides through incubation with very low density lipoproteins (VLDL) or with cholesterol through incubation with aggregated LDL (AgLDL). We then analyzed how foam cell lipid content affected secretion of three pro-inflammatory cytokines: interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and of one chemokine: interleukin-8 (IL-8), all of which are considered pro-inflammatory, pro-atherosclerotic, and are expressed by cells in atherosclerotic tissue. Results Formation of triglyceride-loaded foam cells resulted in a four-fold increase in basal IL-1β secretion, whereas cholesterol loading lacked significant effect on IL-1β secretion. In contrast, secretion of TNF-α and IL-6 decreased significantly following both cholesterol and triglyceride loading, with a similar trend for secretion of IL-8. Lipid loading did not affect cell viability or expression of caspase-3, and did not significantly affect macrophage ability to respond to stimulation with exogenous TNF-α. Conclusion Lipid loading of primary human macrophages resulted in altered cytokine secretion from cells, where effects were similar regardless of neutral lipid composition of cells. The exception was IL-1β, where triglyceride, but not cholesterol, lipid loading resulted in a stimulation of basal secretion of the cytokine. It is apparent that macrophage cytokine secretion is affected by lipid loading by lipoproteins other than OxLDL. As both VLDL and AgLDL have been found in the vessel wall, macrophage cytokine response to uptake of these lipoproteins may have a direct effect on atherosclerotic development in vivo. However, macrophage neutral lipid amount and composition did not affect cellular activation by exogenous TNF-α, making it likely that lipoprotein lipid loading can affect foam cell cytokine secretion during basal conditions but that the effects can be overruled by TNF-α during acute inflammation.

Background: Inflammation and immune responses are considered to be very important in the pathogenesis of atherosclerosis. Lipid accumulation in macrophages of the arterial intima is a characteristic feature of atherosclerosis which can influence the inflammatory potential of macrophages. We studied the effects of lipid loading on the regulation of TNF expression in human monocyte-derived macrophages. Results: In macrophages incubated with acetylated low density lipoprotein (ac-LDL) for 2 days, mRNA expression of TNF in cells stimulated with TNF decreased by 75%. In cell cultures stimulated over night with IL-1β, lipid loading decreased secretion of TNF into culture medium by 48%. These results suggest that lipid accumulation in macrophages makes them less responsive to inflammatory stimuli. Decreased basal activity and inducibility of transcription factor AP-1 was observed in lipid-loaded cells, suggesting a mechanism for the suppression of cytokine expression. NF-κB binding activity and inducibility were only marginally affected by ac-LDL. LDL and ac-LDL did not activate PPARγ. In contrast, oxidized LDL stimulated AP-1 and PPARγ but inhibited NF-κB, indicating that the effects of lipid loading with ac-LDL were not due to oxidation of lipids. Conclusions: Accumulation of lipid, mainly cholesterol, results in down-regulation of TNF expression in macrophages. Since monocytes are known to be activated by cell adhesion, these results suggest that foam cells in atherosclerotic plaques may contribute less potently to an inflammatory reaction than newly arrived monocytes/macrophages.

A radioimmunoassay for triiodothyronine T3 and thyroxine T4 without any manual separation is described. By the use of an aqueous two-phase system the free hormone was separated from the immunologically bound fraction and lifted out of the counting area of the gamma counter. The coefficient of correlation between results obtained with this method and with a conventional RIA was 0.97 and 0.93 for T3 and T4, respectively.

Smooth muscle cells were isolated enzymatically from adult human arteries, grown in primary culture in medium containing 10% whole blood serum, and studied by transmission electron microscopy and [3H]thymidine autoradiography. In the intact arterial wall and directly after isolation, each smooth muscle cell had a nucleus with a wide peripheral zone of condensed chromatin and a cytoplasm dominated by myofilament bundles with associated dense bodies. After 1-2 days of culture, the cells had attached to the substrate and started to spread out. At the same time, a characteristic fine-structural modification took place. It included nuclear enlargement, dispersion of the chromatin and formation of large nucleoli. Moreover, myofilament bundles disappeared and an extensive rough endoplasmic reticulum and a large Golgi complex were organized in the cytoplasm. This morphological transformation of the cells was completed in 3-4 days. It was accompanied by initiation of DNA replication and mitosis. The observations demonstrate that adult human arterial smooth muscle cells, when cultivated in vitro, pass through a phenotypic modulation of the same type as arterial smooth muscle cells from experimental animals. This modulation gives the cells morphological and functional properties resembling those of the modified smooth muscle cells found in fibroproliferative lesions of atherosclerosis. Further studies of the regulation of smooth muscle phenotype and growth may provide important clues for a better understanding of the pathogenesis of atherosclerosis.