Carotid Artery Remodeling Research Articles

Visit-To-Visit BP Variability in the Elderly - Associations with Cognitive Dysfunction and Carotid Artery Remodeling

In the high risk elderly, exaggerated visit-to-visit BP variability was significant indicators for cognitive impairment independently of the average BP level. This relationship was interacted by arterial remodeling.

Preferential secretion of collagen type 3 versus type 1 from adventitial fibroblasts stimulated by TGF-β/Smad3-treated medial smooth muscle cells

Restenosis, or arterial lumen re-narrowing, occurs in 30–50% of the patients undergoing angioplasty. Adaptive remodeling is the compensatory enlargement of the vessel size, and has been reported to prevent the deleterious effects of restenosis. Our previous studies have shown that elevated transforming growth factor (TGF-β) and its signaling protein Smad3 in the media layer induce adaptive remodeling of angioplastied rat carotid artery accompanying an increase of total collagen in the adventitia. In order to gain insights into a possible role of collagen in Smad3-induced adaptive remodeling, here we have investigated a mechanism of cell–cell communication between medial smooth muscle cells (SMCs) and adventitial fibroblasts in regulating the secretion of two major collagen subtypes. We have identified a preferential collagen-3 versus collagen-1 secretion by adventitial fibroblasts following stimulation by the conditioned medium from the TGF-β1-treated/Smad3-expressing medial smooth muscle cells (SMCs), which contained higher levels of CTGF and IGF2 as compared to control medium. Treating the TGF-β/Smad3-stimulated SMCs with an siRNA to either CTGF or IGF2 reversed the effect of conditioned media on preferential collagen-3 secretion from fibroblasts. Moreover, recombinant CTGF and IGF2 together stimulated adventitial fibroblasts to preferentially secrete collagen-3 versus collagen-1. This is the first study to identify a preferential secretion of collagen-3 versus collagen-1 from adventitial fibroblasts as a result of TGF-β/Smad3 stimulation of medial SMCs, and that CTGF and IGF2 function together to mediate this signaling communication between the two cell types.

Dysfunction in elastic fiber formation in fibulin-5 null mice abrogates the evolution in mechanical response of carotid arteries during maturation

Elastin fragmentation is a common characteristic of vascular diseases, such as abdominal aortic aneurysms, peripheral arterial disease, and aortic dissection. Examining growth and remodeling in the presence of dysfunctional elastic fibers provides insight into the adaptive or maladaptive changes that tissues undergo in compensating for structural deficiencies. This study used the maturation of fibulin-5 knockout (KO) and wild-type mice to study the effects of fragmented elastic fibers on the growth and remodeling of carotid arteries. The microstructural content and organization and the biaxial mechanical behavior of common carotid arteries were measured, and parameter estimation performed from KO and WT mice aged 3, 4, 8, and 13 wk. Gross measurements and biaxial tests revealed significant differences in pressure-diameter behavior, in vivo axial stretch, opening angle, compliance, and wall stresses during maturation of wild-type arteries, but little change in these values in KO mice. Multiphoton microscopy used to image collagen fibers across the vessel wall in pressurized and stretched arteries suggests that there is little variation in fiber angles between different ages. Parameter estimation revealed significant differences in material parameters between genotypes and age groups. This study suggests that neonatal formation and cross-linking of functional elastic fibers, followed by increases in artery size due to growth with little remodeling of the elastic fibers, endow arteries with large distensibility and contribute to the evolution of mechanical behavior of arteries during maturation. Dysfunction in neonatal formation of elastic fibers abrogates many of the changes in mechanical response that take place during the maturation.

A gene-centric study of common carotid artery remodelling

BackgroundExpansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. MethodsGenetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Resultsrs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. ConclusionsCommon variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

Different Type of Carotid Arterial Wall Remodeling in Rheumatoid Arthritis Compared with Healthy Subjects: A Case-Control Study

Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, but mechanisms behind this increased risk have not been fully elucidated. Carotid arterial remodeling is the change of structural properties in response to hemodynamic or metabolic factors aimed at keeping wall stress within certain limits. This process might become maladaptive when stress on the arterial wall increases beyond these limits. We investigated whether maladaptive carotid arterial remodeling is present in RA compared with control subjects. The 2 cohorts were 96 patients with RA and 274 healthy subjects, who were investigated cross-sectionally. Carotid intima-media thickness (cIMT) and interadventitial diameter (IAD) were assessed by B-mode carotid ultrasonography. Lumen diameter (LD), circumferential wall stress (CWS), and circumferential wall tension (CWT) were calculated. Linear regression analyses were used to investigate the association between presence of RA and carotid arterial remodeling. Compared with healthy subjects, RA was associated with a 0.40 mm (9.3%) greater LD, 0.41 mm (7.8%) greater IAD, 10% higher CWS, and 8% higher CWT. The groups had comparable cIMT. Associations remained similar after exclusion of patients with prior CV disease and after adjustment for demographic factors and CV risk factors. RA is associated with maladaptive outward carotid arterial remodeling. These results are relevant because maladaptive outward remodeling is associated with plaque instability and rupture. These results indicate an alternative pathway, beyond the traditional CV risk factors, in RA that amplifies the CV risk.

EFFECTS OF HIGH-SALT DIET ON THE REMODELLING OF CAROTID ARTERIES AND THE INTERVENTION OF TELMISARTAN IN WISTAR RATS

ObjectivesTo study the influence of high salt diet on blood pressure and carotid artery remodelling and the intervention of telmisartan in Wiatar rats.Methods60 Wistar rats were fed a normal salt...

ROLE OF TGF-β1/SMADS PATHWAY IN CAROTID ARTERY REMODELLING AND PREVENTION OF ENALAPRIL AND AMLODIPINE IN RENOVASCULAR HYPERTENSIVE RATS

ObjectivesTo investigate the role of TGF-β1/Smads pathway in carotid artery remodelling in renovascular hypertensive rats and the prevention of enalapril and amlodipine.MethodsThe renovascular hypertensive rats (RHR) developed by ‘two-kidney and...

EFFECTS OF ENALAPRIL AND IRBESARTAN ON CAROTID ARTERY REMODELLING AND TGF-β1/SMADS PATHWAY IN RENOVASCULAR HYPERTENSIVE RATS

ObjectivesTo investigate the effects of single-drug or combination therapy of enalapril and irbesartan on carotid artery remodelling and TGF-β1/Smads signal pathway.MethodsRenovascular hypertensive rats (RHR) developed by ‘two-kidney and one-clip’ method...

Role of TGF-β1/Smads pathway in carotid artery remodeling in renovascular hypertensive rats and prevention by Enalapril and Amlodipine

ObjectiveTo investigate the role of transforming growth factor-β1 (TGF-β1), Smad2/3 and Smad7 expressions in carotid artery remodeling in renovascular hypertensive rats, and also the therapeutic effect of Enalapril and Amlodipine.MethodsThe renovascular hypertensive rat (RHR) models with “two-kidney and one-clip” were established, including model group (n = 6), sham-operated group (n = 6), Enalapril group (10 mg/kg per day, n = 6), Amlodipine group (5 mg/kg per day, n = 6) and combination group (Amlodipine 2.5 mg/kg per day + Enalapril 5mg/kg per day, n = 6). The medication were continuous administrated for six weeks. Carotid artery morphological and structural changes in the media were observed by HE staining, Masson staining and immuno histochemical staining. Media thickness (MT), MT and lumen diameter ratio (MT/LD), and the expression levels of media α-smooth muscle actin (α-actin), proliferating cell nuclear antigen (PCNA), TGF-β1, phosphorylated Smad2/3 (p-Smad2/3) and Smad7 in carotid arteries were measured.ResultsThe media of carotid arteries in RHR model group was significantly thickened, the volume of smooth muscle cell was increased, and the array was in disorder; MT, MT/LD, the proliferation index of smooth muscle cell and collagen fiber area percentage of carotid arteries in the model group were significantly higher than those in the sham-operated group (P < 0.01). Compared to sham-operated group, the model group had significantly higher expressions of TGF-β1 and p-Smad2/3 (P < 0.05) and lower Smad7 expression. Both Enalapril and Amlodipine improved smooth muscle hypertrophy and collagen deposition, reduced RHR carotid MT, MT/LD, proliferation index of smooth muscle cell, collagen fiber area percentage and the expressions of TGF-β1 and p-Smad2/3 (P < 0.05), increased Smad7 expression (P < 0.05). Moreover, the combination treatment of Enalapril and Amlodipine had significantly better effects than single Amlodipine group (P < 0.05), but not single Enalapril group.ConclusionsTGF-β1/Smads pathway may participate in the mechanism of carotid artery remodeling in RHR; the role of Amlodipine and Enalapril in inversing carotid artery remodeling may be related to the change of TGF-β1/Smads pathway, the combination treatment of Amlodipine and Enalapril had better effects than single administration of Amlodipine.

Vascular Endothelial Dysfunction in β-Thalassemia Occurs Despite Increased eNOS Expression and Preserved Vascular Smooth Muscle Cell Reactivity to NO

AimsThe hereditary β-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of β-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments.Methods and ResultsVascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of β-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside) produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO). While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS) in β-thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of β-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall.ConclusionsA complex vasculopathy was identified in untransfused β-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression.

Effects of an intensive behavioral weight loss intervention consisting of caloric restriction with or without physical activity on common carotid artery remodeling in severely obese adults

ObjectiveObesity increases cardiovascular disease risk and adversely affects vascular structure and function. Few studies have evaluated the vascular effects of non-surgical weight reduction in the severely obese. We hypothesized that weight loss and improvements in cardiometabolic factors would reduce common carotid artery intima-media thickness (CIMT) and inter-adventitial diameter (AD) in severely obese adults. MethodsWe performed carotid ultrasound and measured cardiometabolic factors in 90 severely obese participants (body mass index (BMI)≥35kg/m2, age 30–55) at baseline and 6months in a randomized clinical trial of dietary intervention with (n=45) or without (n=45) physical activity. ResultsThe achieved weight loss (mean=8%) did not differ significantly by intervention group (P=0.10) and resulted in a 0.07mm mean decrease in AD (P=0.001). AD change was positively correlated with changes in BMI, waist circumference, abdominal visceral and subcutaneous fat, and body fat mass, and AD decreased more in men (P<0.05 for all). After multivariable adjustment, changes in BMI (P=0.03) and abdominal subcutaneous fat (P=0.04) were significant determinants of AD change. Although CIMT did not decrease significantly overall (-0.008mm, P=0.16), individuals who lost at least 5% of their body weight experienced a significant mean reduction in CIMT of 0.02mm (P=0.002). CIMT change was positively correlated with changes in BMI, waist circumference, fat-free mass, leptin, and insulin (P<0.05 for all). After multivariable adjustment, insulin reduction remained a significant determinant of CIMT decrease (P=0.03). ConclusionA 6 month intensive behavioral intervention can significantly reverse metabolic and vascular abnormalities in severely obese adults.

Low-grade inflammation, but not endothelial dysfunction, is associated with greater carotid stiffness in the elderly

Biomarkers of low-grade inflammation and endothelial dysfunction are associated with cardiovascular disease. Arterial stiffening may be a mechanism through which low-grade inflammation and (or) endothelial dysfunction lead to cardiovascular disease. Therefore, we investigated whether low-grade inflammation and endothelial dysfunction were associated with greater carotid stiffness in a population-based cohort of elderly individuals. We determined biomarkers of low-grade inflammation (C-reactive protein, serum amyloid A, interleukin 6, interleukin 8, tumour necrosis factor α and soluble intercellular adhesion molecule 1), and of endothelial dysfunction (von Willebrand factor, soluble vascular cell adhesion molecule 1, soluble endothelial selectin, soluble thrombomodulin, soluble intercellular adhesion molecule 1 and flow-mediated dilation), and combined these into mean z-scores (n = 572; women = 286; age 67.5 ± 6.6 years). Additionally, we determined by ultrasonography carotid diameter, distension, pulse pressure and intima-media thickness. Carotid stiffness indices were determined by calculation of the distensibility and compliance coefficient, Young's elastic modulus and β stiffness index. The study population was characterized by a high prevalence of cardiovascular disease (46%), hypertension (66%) and the use of lipid-lowering (16%) and antihypertensive (34%) medication. After adjustment for the above in addition to sex, age, glucose tolerance status and current smoking, the low-grade inflammation z-score was positively associated with Young's elastic modulus [β (95% confidence interval) 0.080 (0.021-0.139), P = 0.008]. This association was primarily driven through greater diameter. After adjustment for the variables above, the endothelial dysfunction z-score was not associated with carotid stiffness. These data suggest that low-grade inflammation, in the elderly, plays an important role in carotid artery remodelling and stiffening.

Carotid and brachial arterial enlargement in postmenopausal women with hypertension

The aim of this study was to test whether systemic hypertension influences brachial and carotid artery remodeling in postmenopausal women. A secondary aim was to evaluate the possible role of pulse pressure. We enrolled 100 postmenopausal women affected by hypertension (cases) and 100 women with blood pressure within the reference range (controls) matched for age and body mass index because the influence of these variables on artery diameter is well known. Clinical and biochemical parameters were also assessed. All women underwent B-mode ultrasonography to measure the carotid and brachial artery diameter. The case group had significantly larger brachial and common carotid artery diameters than control groups (P < 0.001). This result did not change after correction for confounding variables. Indeed, the women with hypertension had higher glucose and insulin levels and greater carotid atherosclerosis prevalence than did the control population. A multivariate linear regression analysis showed a correlation between artery diameters and hypertension status in the whole population. To evaluate the influence of pulse pressure, each group (cases and controls) was divided into two subgroups, according to the group-specific pulse pressure median. The women with a pulse pressure rate higher than the median value had larger artery diameters compared with those with lower pulse pressure rates in both groups with and without hypertension. Hypertension can promote generalized artery enlargement, and pulse pressure also plays a role in artery remodeling. Interestingly, pulse pressure seems to influence arterial diameter in individuals with blood pressure within the reference range. The role of hypertension in artery remodeling behind age and the body mass index requires further investigations on the mechanisms underlying remodeling.

Effects of an intensive behavioral weight loss intervention consisting of caloric restriction with or without physical activity on common carotid artery remodeling in severely obese adults

Effects of an intensive behavioral weight loss intervention consisting of caloric restriction with or without physical activity on common carotid artery remodeling in severely obese adults

Body composition, C-reactive protein, carotid artery remodeling and subclinical atherosclerosis in a general Taiwanese population

Obesity, an escalating problem worldwide, increases the risk of serious disease, particularly atherosclerosis. A community-based cross-sectional study was designed to screen for undetected atherosclerosis. High-sensitivity C-reactive protein (hs-CRP), the presence of the metabolic syndrome (MetS), and ultrasound studies to detect fatty liver and measure carotid intimal-medial thickness were performed. A total of 1,005 subjects (595 men and 410 women; mean age of 52.4 ± 11.1 years) were included in the final study cohort. 237 subjects (23.7%) fulfilled National Cholesterol Education Program Adult Treatment Panel ATP-III criteria for MetS. Significant differences between female and male subjects were noted in body mass index (BMI), % body fat mass (Fat%), waist-to-hip ratio, waist circumference, fasting glucose levels, triglyceride levels, fatty liver, and carotid artery changes (P < 0.05). When female subjects were classified by hs-CRP levels, significant differences were reported among the three groups in age, BMI, Fat%, waist-to-hip ratio, waist circumference, blood pressure, fasting glucose, HDL, triglycerides, fatty liver grade and common carotid artery changes (P < 0.05). In this study, high hs-CRP was associated with increased cholesterol and cardiovascular changes supporting the idea that it may be a useful biomarker for detecting early asymptomatic vascular and coronary heart disease resulting from obesity.

Effects of high-salt diet on carotid artery remodeling and the intervention of telmisartan in Wistar rats

Objective: To study the influence of high salt diet on carotid artery remodeling and the intervention of telmisartan in Wistar rats. Methods: 60 Wistar rats were divided into 3 groups: a normal salt diet (NSD: 0.5% NaCl), high salt diet (HSD: 8% NaCl) and HSD+telmisartan for 24weeks. Tail-cuff blood pressure was measured every 2weeks. Media thickness (MT), lumen diameter (LD), MT and LD ratio (MT/LD) and collagen area percentage of carotid arteries were measured by HE and Masson staining. The protein expression of α-smooth muscle actin(α-SMA), TGF-β1, smad2/3, smad7, AngII, AT1R, AT2R and PCNA of carotid artery media were detected by immunohistochemistry.

Integrin-Targeted Imaging of Inflammation in Vascular Remodeling

Inflammation plays a key role in the development of vascular diseases. Monocytes and macrophages express α(v)β(3) integrin. We used an α(v) integrin-specific tracer, (99m)Tc-NC100692, to investigate integrin-targeted imaging for detection vessel wall inflammation. The binding of a fluorescent homologue of NC100692 to α(v)β(3) on human monocytes and macrophages was shown by flow cytometry. Vessel wall inflammation and remodeling was induced in murine carotid arteries through adventitial exposure to CaCl(2). NC100692 micro single photon computed tomography/CT imaging was performed after 2 and 4 weeks and showed significantly higher uptake of the tracer in CaCl(2)-exposed left carotids compared with sham-operated contralateral arteries. Histological analysis at 4 weeks demonstrated significant remodeling of left carotid arteries and considerable macrophage infiltration, which was confirmed by real-time polymerase chain reaction. There was no significant difference in normalized α(v), β(3), or β(5) mRNA expression between right and left carotid arteries. Finally, NC100692 uptake strongly correlated with macrophage marker expression in carotid arteries. NC100692 imaging can detect vessel wall inflammation in vivo. If further validated, α(v)-targeted imaging may provide a noninvasive approach for identifying patients who are at high risk for vascular events and tracking the effect of antiinflammatory treatments.

Attenuated Age-related Carotid Arterial Remodeling In Adults With High Level Of Cardiorespiratory Fitness

PURPOSE: Cardiorespiratory fitness (CRF) is independently associated with reduced risk of cardiovascular disease. Carotid arterial remodeling, which is derived from the interplay between carotid luminal dilation and wall thickening, is also an independent predictor of cardiovascular events. We hypothesized that high CRF may be associated with reduced age-related carotid arterial remodeling. This cross-sectional study was performed to determine the relationships between CRF and age-related luminal dilation and wall thickening. METHODS: A total of 771 adults (180 men and 591 women), under age 40 (young), 40-59 (middle-aged), and over age 60 (older) participated in this study. Subjects in each age category were divided into either high (fit) or low (unfit) CRF groups based on VO2peak. Carotid artery intima-media thickness (IMT) and lumen diameter were measured on ultrasound images. Carotid wall mass was calculated as ρL(πRe2-Ri2). RESULTS: Two-way ANOVA indicated a significant interaction (P<0.01) between age and CRF in determining IMT, lumen diameter, and wall mass. In older subjects, IMT, lumen diameter, and wall mass were significantly lower (P<0.05) in the fit than in the unfit group (IMT, 0.69±0.01 vs. 0.74±0.01 mm; lumen diameter, 5.99±0.06 vs. 6.28±0.06 mm; wall mass, 7.41±0.25 vs. 8.71±0.25 mm3). Carotid IMT (r=-0.24, P<0.05), luminal diameter (r=-0.28, P<0.01), and wall mass (r=-0.30, P<0.01) were correlated with VO2peak in older subjects. There were no significant relationships in young or middle-aged subjects. Multiple regression analysis indicated that the value of VO2peak was independently correlated with carotid IMT, lumen diameter and wall mass. CONCLUSIONS: The present study indicated that a high level of CRF is associated with reduced age-related wall thickening and luminal dilation in the carotid artery. This study was supported by a Grant-in-Aid for Scientific Research (#20300231, M. Miyachi, #18200041, H. Shibayama) and a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan (M. Miyachi).

Attenuated Age-Related Carotid Arterial Remodeling in Adults with a High Level of Cardiorespiratory Fitness

Cardiorespiratory fitness (CRF) is independently associated with a reduced risk of cardiovascular disease. Carotid arterial remodeling, which is derived from the interplay between carotid luminal dilation and wall thickening, is also an independent predictor of cardiovascular events. We hypothesized that high CRF may be associated with reduced age-related carotid arterial remodeling. This cross-sectional study was performed to determine the relationships between CRF and age-related luminal dilation and wall thickening. A total of 771 adults (180 men and 591 women), under age 40 (young), 40-59 (middle-aged), and over age 60 (older) participated in this study. Subjects in each age category were divided into either high (fit) or low (unfit) CRF groups based on VO(2peak). Carotid artery intima-media thickness (IMT) and lumen diameter were measured on ultrasound images. Carotid wall mass was calculated as ρL(πRe(2)-Ri(2)). Two-way ANOVA indicated a significant interaction (p < 0.01) between age and CRF in determining IMT, lumen diameter, and wall mass. In older subjects, IMT, lumen diameter, and wall mass were significantly lower (p < 0.05) in the fit than in the unfit group (IMT, 0.69±0.01 vs. 0.74±0.01 mm; lumen diameter, 5.99±0.06 vs. 6.28±0.06 mm; wall mass, 7.41±0.25 vs. 8.71±0.25 mm(3)). Multiple regression analysis indicated that the value of VO(2peak) was independently correlated with carotid IMT, lumen diameter and wall mass. The present study indicated that a high level of CRF is associated with reduced age-related wall thickening and luminal dilation in the carotid artery.

Alcohol Inhibits Smooth Muscle Cell Proliferation via Regulation of the Notch Signaling Pathway

To determine the role of Notch signaling in mediating alcohol's inhibition of smooth muscle cell (SMC) proliferation. Treatment of human coronary artery SMCs with ethanol (EtOH) decreased Notch 1 mRNA and Notch 1 intracellular domain protein levels, in the absence of any effect on Notch 3. EtOH treatment also decreased C-promoter binding factor-1 (CBF-1)/recombination signal-binding protein (RBP)-jk promoter activity and Notch target gene (hairy related transcription factor [HRT-1] or HRT-2) expression. These effects were concomitant with an inhibitory effect of EtOH on SMC proliferation. Overexpression of constitutively active Notch 1 intracellular domain or human hairy related transcription factor-1 (hHRT-1) prevented the EtOH-induced inhibition of SMC proliferation. In vivo, Notch 1 and HRT-1 mRNA expression was increased after ligation-induced carotid artery remodeling. The vessel remodeling response was inhibited in mice that received "moderate" amounts of alcohol by gavage daily; intimal-medial thickening was markedly reduced, and medial and neointimal SMC proliferating cell nuclear antigen expression was decreased. Moreover, Notch 1 and HRT-1 expression, induced after ligation injury, was inhibited by moderate alcohol consumption. EtOH inhibits Notch signaling and, subsequently, SMC proliferation, in vitro and in vivo. The modulation of Notch signaling in SMCs by EtOH may be relevant to the cardiovascular protective effects of moderate alcohol consumption purported by epidemiological studies.