OBJECTIVEVascular calcification is the consequence of the complex interaction between genetic, environmental, and vascular factors, which ultimately lead to the deposition of calcium in the tunica intima (atherosclerotic calcification) or tunica media (Mönckenberg's sclerosis). Vascular calcification is also closely related to other pathologies, such as diabetes mellitus, dyslipidemia, and chronic kidney disease. It has been concluded that the degree of vascular calcification may vary from person to person, even if the associated pathologies and environmental factors are the same. Therefore, this suggests an important genetic contribution to the development of vascular calcification. This review aimed to find the most recent evidence about vascular calcification pathophysiology regarding the genetic aspects and molecular pathways.

DATA SOURCESWe conducted an exhaustive search in Scopus, EBSCO, and PubMed with the keywords "genetics and vascular calcification", "molecular pathways, genetic and vascular calcification" and included the main articles from January 1995 up to August 2016. We focused on the most recent evidence about vascular calcification pathophysiology regarding the genetic aspects and molecular pathways.

STUDY SELECTIONThe most valuable published original and review articles related to our objective were selected.

RESULTSVascular calcification is a multifactorial disease; thus, its pathophysiology cannot be explained by a single specific factor, rather than by the result of the association of several genetic variants, molecular pathway interactions, and environmental factors that promote its development.

CONCLUSIONAlthough several molecular aspects of this mechanism have been elucidated, there is still a need for a better understanding of the factors that predispose to this disease.

Diabetes Mellitus ; metabolism ; physiopathology ; Dyslipidemias ; metabolism ; physiopathology ; Humans ; Kidney Failure, Chronic ; metabolism ; physiopathology ; Renal Insufficiency, Chronic ; metabolism ; physiopathology ; Tunica Intima ; metabolism ; physiopathology ; Tunica Media ; metabolism ; physiopathology ; Vascular Calcification ; metabolism ; physiopathology

Vascular remodeling is being recognized as a fundamental process during atherosclerosis and restenosis. Cumulative studies have demonstrated that extracellular matrix (ECM) degrading enzymes play a critical role during vascular remodeling. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family is a recently identified metalloproteinase family which also has capacity to degrade ECM. ADAMTS family consists of 19 members and has been linked to a variety of physiological processes including development, angiogenesis, coagulation etc. Aberrant expression or function of ADAMTS members have been implicated to many disease states such as arthritis, cancer, thrombocytopenic purpura, but barely described with regard to cardiovascular disease. This review summarizes the recent advance with respect to the role of ADAMTS-7 in vascular remodeling. We review the structure, tissue distribution, substrate, expression and regulation of ADAMTS-7, especially highlight the fine tune by ADAMTS-7 of its substrate cartilage oligomeric matrix protein (COMP) in maintaining vascular homeostasis. By use of rat carotid artery balloon injury model to mimic vascular injury in vivo, we found that ADAMTS-7 protein was accumulated preferentially in neointima and mainly localized in vascular smooth muscle cells (VSMCs). Adenovirus-elicited ADAMTS-7 overexpression greatly accelerated VSMCs migration and proliferation both in vivo and in vitro, and subsequently aggravated neointima thickening post-injury. Conversely, siRNA-mediated ADAMTS-7 knock down bona fide inhibited VSMCs migration and proliferation in cultured VSMCs and injured arteries, and ultimately ameliorated neointima area. Further studies demonstrated that ADAMTS-7 facilitated VSMCs migration through degradation of its substrate COMP. Moreover, we elucidated that COMP has the capacity to maintain the contractile phenotype of VSMCs through interacting with integrin alpha7beta1. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and postangioplasty restenosis.
ADAM Proteins ; physiology ; ADAMTS7 Protein ; Animals ; Atherosclerosis ; physiopathology ; Carotid Artery Injuries ; metabolism ; pathology ; Cartilage Oligomeric Matrix Protein ; Cell Movement ; Cell Proliferation ; Extracellular Matrix Proteins ; metabolism ; physiology ; Glycoproteins ; physiology ; Humans ; Matrilin Proteins ; Muscle, Smooth, Vascular ; metabolism ; pathology ; Rats ; Tunica Intima ; metabolism ; pathology

OBJECTIVETo explore the relationship of Chinese medicine (CM) syndrome with carotid intima-media thickness (CIMT) and endothelium-dependent vasodilatation function (EDVF) in patients with hypertensive disease (HD) for providing an objective basis of syndrome differentiation in HD patients.

METHODSColor Doppler's ultrasound was used to measure the endothelium-dependent flow-mediated dilation (FMD) of brachial artery and carotid intima-media thickness (CIMT) in 60 HD patients (the HD group) and 30 normal controls (the control group). And the relationship of the outcomes with Chinese medicine syndrome types in patients was analyzed statistically.

RESULTSFMD was lower and CIMT was higher in HD patients of all syndrome types than those in the control group respectively (P<0.01). Comparison between patients of different syndrome types showed that FMD was higher in patients of Gan-fire exuberance type and yin-deficiency and yang-hyperaction type than in those of both yin-yang deficiency type and phlegm-dampness stagnancy type (P<0.01, P<0.05), while CIMT in patients of Gan-fire exuberance type was the lowest in all types, and that in yin-deficiency and yang-hyperaction type was lower than in yin-yang deficiency type (P<0.01).

CONCLUSIONCIMT and FMD may be used as a reference index for CM syndrome differentiation in HD patients.

Adult ; Aged ; Carotid Intima-Media Thickness ; Case-Control Studies ; Endothelium-Dependent Relaxing Factors ; Female ; Humans ; Hypertension ; diagnosis ; diagnostic imaging ; physiopathology ; Male ; Medicine, Chinese Traditional ; methods ; Middle Aged ; Tunica Intima ; diagnostic imaging ; Tunica Media ; diagnostic imaging

OBJECTIVES: The aim of this study was to investigate the association of blood pressure levels with the common carotid artery intima-media thickness (CCA-IMT) and carotid plaques. METHODS: Data were obtained from 2,635 subjects, aged 50 years and over, who participated in the Community Health Survey (a population-based, cross-sectional study) in Dong-gu, Gwangju city between 2007 and 2008. Participants were categorized into three groups according to blood pressure levels; normotensives (<120/80 mmHg), prehypertensives (120-139/80-89 mmHg), and hypertensives (> or =140/90 mmHg). Prehypertensives were further categorized as low prehypertensives (120-129/80-84 mmHg) and high prehypertensives (130-139/85-89 mmHg). Carotid intima-media thickness and plaques were evaluated with a high-resolution B-mode ultrasound. Statistical analyses were performed using chi-square test, ANOVA, and multiple logistic regression. RESULTS: Prehypertensives had significantly greater maximal CCA-IMT values than normotensives, with a multivariate adjusted odds ratio of 1.78 (95% CI=1.36-2.32) for abnormal CCA-IMT (maximal CCA-IMT > or =1.0 mm), and 1.45 (95% CI=1.19-1.77) for carotid plaques. The multivariate adjusted odds ratio of low prehypertensives was 1.64 (95% CI=1.21-2.21) for abnormal CCA-IMT, and 1.30 (95% CI=1.04-1.63) for carotid plaques compared with normotensives. Subject with hypertension had higher frequency of abnormal CCA-IMT (odds ratio, 2.18; 95% CI=1.49-3.18), and carotid plaques (odds ratio, 1.98; 95% CI=1.46-2.67) compared with normotensives after adjustment for other cardiovascular risk factors. CONCLUSIONS: Our results indicate that there is a significant increase in the prevalence of carotid atherosclerosis in subjects with prehypertension (even in low prehypertensives) compared with normotensive subjects. Further studies are required to confirm the benefits and role of carotid ultrasonography in persons with prehypertension.
Aged ; *Blood Pressure ; Carotid Artery Diseases/physiopathology ; Carotid Artery, Common/*pathology/ultrasonography ; Carotid Stenosis/pathology ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Prevalence ; Tunica Intima/*pathology

Increased intima-media thickness (IMT) and pulse wave velocity (PWV) are noninvasive markers of early arterial wall alteration and are more widely used in adult clinical research. We investigated whether IMT and PWV are useful predictors of cardiovascular risk in hypertensive adolescents. Fifteen hypertensive adolescents (13-18 yr old, systolic BP > or = 140 mmHg, diastolic BP > or = 90 mmHg) and seventeen normotensive subjects were included. Height, weight, obesity index, body mass index (BMI), and fat distribution were obtained from each group. Serum lipid, insulin, vitamine B12, folate, renin, aldosterone, angiotensin-converting enzyme (ACE), and homocysteine levels were compared. The carotid IMT and PWV were measured. Arterial wall compliance and distensibility were calculated with the equation. High systolic blood pressure significantly correlated with height, weight, BMI, obesity index, arm circumference, fat mass, and fat distribution. Hypertensive adolescents had significantly greater cIMT (carotid intima-media thickness) and lower elastic properties such as cross-sectional compliance and distensibility of the carotid artery. The carotid IMT significantly correlated with brachial-ankle PWV. In conclusion, the measurement of carotid IMT and brachial-ankle PWV might be useful to predict the development of atherosclerosis in hypertensive adolescents.
Adolescent ; Arteries/*pathology/physiopathology ; Body Mass Index ; Elasticity ; Female ; Humans ; Hypertension/*pathology/physiopathology ; Male ; Tunica Intima/*pathology/physiopathology ; Tunica Media/*pathology/physiopathology

OBJECTIVETo demonstrate the abnormal intima rotation pattern of the carotid atherosclerosis plaque using velocity vector imaging, and to develop a new method for the clinical mechanical state assessment of the plaque intima.

METHODSThe rotation movement and rotation angle on the serial dynamic ultrasonic short-axis gray scale views of 48 isolated atherosclerosis plaques (i. e., upstream, midstream, and downstream) and nearby reference segments of carotid artery in 46 patients were derived and analyzed using a dedicated velocity vector imaging workstation. The incidence of intima rotation movement and the rotation angle at different sections of the plaque and nearby reference segments before and after the standard grip stress test during systole and diastole respectively were counted and measured.

RESULTSBefore and after the stress test, the intima rotation movement occurred at the majority of the short-axis sections of the plaque and the nearby reference segments during cardiac cycle. Before the stress test, the incidence of intima rotation movement at the upstream section of the plaque during systole was significantly higher than that of reference segment (P = 0.036) The reversal direction of the intima rotation at those sections and reference segment during systole and diastole was demonstrated. After the stress test, the incidence of intima rotation movement at the midstream section of the plaque during diastole was significantly lower than that of reference segment (P = 0.031). The incidence of the intima rotation movement changed at the sections of upstream, midstream, and downstream of the plaque before and after the stress test also were explored (i. e., increased in systole and decreased in diastole) except the reference segment intima.

CONCLUSIONSThe intima rotation movement occurs at the majority of the isolated plaque and nearby reference segment, and the incidences of the intima rotation movement at the plaque is different from that of the reference segment during systole and diastole respectively. The abnormal pattern of intima rotation movement may be used to indicate the unstable mechanical state of the isolated plaque intima.

Carotid Arteries ; diagnostic imaging ; physiopathology ; Carotid Stenosis ; diagnostic imaging ; physiopathology ; Echocardiography, Stress ; Exercise Test ; Humans ; Rotation ; Tunica Intima ; diagnostic imaging ; physiopathology

OBJECTIVES: The aim of this study is to investigate the association between obesity indices (body mass index, weight, waist-hip ratio and waist circumference) in adolescents and the carotid intima-media thickness (C-IMT) in early adulthood. We also wanted to identify the best predictor for C-IMT among these obesity indices. METHODS: This study used community-based prospective cohort study, known as the Kangwha Study, and the data we used were from subjects who were 16-years old in 1996 (defined as "adolescencec") and 25 years-old in 2005 (defined as "early adulthoodc"). The 256 subjects (113 men and 143 women) who were used for analysis participated in both follow-ups, and they underwent B-mode ultrasonography of the carotid arteries at the early adulthood follow-up. Obesity indices were defined as the body mass index, weight, waist-hip ratio and waist circumference. The C-IMT was defined as the mean of the maximal IMT of each common carotid artery. The C-IMT and obesity indices associations were evaluated via multivariable regression, logistic regression and the receiver-operator characteristic curve analyses. RESULTS: In men, all the obesity indices in adolescence were showed to have statistically significant positive association with C-IMT in early adulthood. However, no such relationship was showed in women. On multiple regression and logistic regression analysis, the waist-hip ratio showed the biggest relationship with the C-IMT among the 4 obesity indices. However, there were no statistical significant differences and no best predictor was found. For the women, the obesity incidences and C-IMT showed no relationships. CONCLUSIONS: This study suggested that obesity in adolescence was related to an increase C-IMT in healthy young Korean men.
Adolescent ; Adult ; Blood Glucose/analysis ; Blood Pressure ; Carotid Arteries/*pathology ; Female ; Humans ; Korea/epidemiology ; Lipids/blood ; Male ; Obesity/*pathology/physiopathology ; Prospective Studies ; Sex Factors ; Tunica Intima/*pathology ; Waist-Hip Ratio

AIMTo investigate the relationship between androgen level and the indexes indicating endothelial function in male patients with coronary heart disease (CHD).

METHODSWe registered the following data for 106 50-70-year-old men: age, weight, blood lipid, including total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride, whether a smoker, sugar levels, blood pressure, free testosterone (FT), vascular cell adhesion molecule-1 (VCAM-1) and the intima-media thickness (IMT) of common carotid artery, common carotid diameter, maximum velocity in systolic phase, minimum velocity in diastolic phase and resistant index. Among the 106 men, 51 were patients with CHD. The relationships between FT level, VCAM-1 concentration and IMT were examined, respectively, using a stepwise linear regression technique among all the 106 men.

RESULTSThere was no statistical difference in terms of age, blood pressure, whether a smoker, sugar levels, HDL-C, minimum velocity in diastolic phase, resistant index between male CHD patients and controls; whereas results for weight, total cholesterol, low density lipoprotein cholesterol, triglyceride, VCAM-1 and IMT of male CHD patients were higher than those of controls; FT level and maximum velocity in systolic phase were lower. It was found that among all the objects, FT level was inversely correlated with IMT and VCAM-1 concentration.

CONCLUSIONFT level was inversely correlated with VCAM-1 concentration and IMT which are indicators of endothelial function.

Aged ; Carotid Artery, Common ; diagnostic imaging ; Coronary Disease ; blood ; physiopathology ; Endothelium, Vascular ; physiopathology ; Humans ; Male ; Middle Aged ; Testosterone ; blood ; Tunica Intima ; diagnostic imaging ; Tunica Media ; diagnostic imaging ; Ultrasonography ; Vascular Cell Adhesion Molecule-1 ; blood

OBJECTIVES: Although risk factors for coronary artery disease are also associated with increased carotid intima-media thickness (IMT), there is little information available on the asymptomatic, young adult population. We examined the association between multiple cardiovascular risk factors and the common carotid IMT in 280 young Korean adults. METHODS: The data used for this study was obtained from 280 subjects (130 men and 150 women) aged 25 years who participated in the Kangwha Study follow-up examination in 2005. We measured cardiovascular risk factors, including anthropometrics, blood pressure, blood chemistry, carotid ultrasonography, and reviewed questionnaires on health behaviors. Risk factors were defined as values above the sex-specific 75th percentile of systolic blood pressure, body mass index, total cholesterol/high-density lipoprotein cholesterol ratio, fasting blood glucose and smoking status. RESULTS: The mean carotid IMT+/-standard deviation observed was 0.683+/-0.079 mm in men and 0.678+/-0.067 mm in women (p=0.567) and the evidence of plaque was not observed in any individuals. Mean carotid IMT increased with an increasing number of risk factors(p for trend <0.001) and carotid IMT values were 0.665 mm, 0.674 mm, 0.686 mm, 0.702 mm, and 0.748 mm for 0, 1, 2, 3, and 4 to 5 risk factors, respectively. The odds ratio for having the top quartile carotid IMT in men with 3 or more risk factors versus 0-2 risk factors was 5.09 (95% CI, 2.05-12.64). CONCLUSIONS: Current findings indicate the need for prevention and control of cardiovascular risk factors in young adults and more focus on those with multiple cardiovascular risk factors.
Adult ; Blood Pressure ; Body Weights and Measures ; Cardiovascular Diseases/*epidemiology ; Carotid Arteries/*physiopathology/ultrasonography ; Female ; Health Behavior ; Hematologic Tests ; Humans ; Korea/epidemiology ; Male ; Risk Factors ; Tunica Intima/*physiopathology

OBJECTIVETo investigate the neointima formation and the expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in cuff-induced vascular injury in mouse model, and to examine the effect of angiotensin II type 1 receptor (AT1) blocker, olmesartan, on MCP-1 and TNF-alpha expression and consequently vascular remodeling.

METHODSVascular injury was induced by polyethylene cuff-placement around the mouse femoral artery. Some mice were treated with AT1 receptor blocker, olmesartan, at the dose of 3 mg.kg(-1).day(-1) with an osmotic minipump. Neointima formation and the proliferation of vascular smooth muscle cells (VSMCs) were measured by morphometric analysis and bromodeoxyuridine (BrdU) incorporation. MCP-1 and TNF-alpha expression was detected by Western blot and immunohistochemical staining.

RESULTSWe observed neointima formation 14 days after cuff placement as well as VSMCs proliferation in the media and neointima. Cuff placement also induced MCP-1 and TNF-alpha expression in the media and neointima that the VSMCs specifically existed. Treatment of mice with olmesartan at a dose of 3 mg.kg(-1).day(-1), which did not influence systolic blood pressure, significantly decreased neointima formation and the proliferation of VSMCs. Olmesartan also inhibited MCP-1 and TNF-alpha expression in the injured arteries.

CONCLUSIONSOur results demonstrate that blockade of AT1 receptor inhibits MCP-1 and TNF-alpha expression and thereby improves vascular remodeling.

Analysis of Variance ; Animals ; Blotting, Western ; Cell Division ; drug effects ; physiology ; Cells, Cultured ; Chemokine CCL2 ; analysis ; Disease Models, Animal ; Imidazoles ; pharmacology ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred C57BL ; Monocytes ; cytology ; drug effects ; Muscle, Smooth, Vascular ; cytology ; drug effects ; Neovascularization, Physiologic ; drug effects ; physiology ; Olmesartan Medoxomil ; Probability ; Sensitivity and Specificity ; Tetrazoles ; pharmacology ; Tumor Necrosis Factor-alpha ; analysis ; drug effects ; Tunica Intima ; drug effects ; pathology ; Vascular Diseases ; physiopathology