Vascular Wall Thickness Research Articles

Impact of dental implant insertion method on the periimplant epithelial seal: Experimental study on dogs

There is a controversial opinion among implantologists on the method of dental implantation that provides more favourable response of soft and bone tissues. The aim of this study was to pathohistologicaly compare the influences of one- and two-phase implant surgical methods on the periimplant epithelial tissues. The experiment was performed on 10 dogs. Eight weeks following tooth extractions implants were inserted using one phase method on the right side of the mandible, and two-phase method on the left one. Three months after implantation the animals were sacrificed. Contact regions of epithelial and subepithelial tissues and implants were pathohistologicaly examined, the elements of analysis were scored and compared. Epithelial tissue was not found in the two samples of one-phase implants, while in the remainder of samples the structure of basal membrane was preserved, massive inflammatory infiltrate was found in one, and partial necrosis was found in three samples. Epithelial tissue was not found in the three samples of two-phase implants, in three samples the structure of basal membrane was intact, while in three remained samples the membrane could not be detected; moderate inflammatory infiltrate was found in four samples and massive inflammatory infiltrate in both two remained samples; tissue necrosis, which was observed in the half of the samples, was complete. In subepithelial gingival tissues around one-phase implants the number of blood vessels was increased in three samples, accompanied by the thickening and dilatation of vascular walls, proliferation of blood elements, altered vascular walls and inflammatory cell infiltrate was found in four samples. On the base of the analized characteristics of epithelial and subepithelial tissues in contact with dental implants, one-phase method of implantation showed a more favorable tissue response.

A piece in the puzzle of intrauterine fetal death: Pathological findings in placentas from term and preterm intrauterine fetal death pregnancies

Objective. To compare pathological findings of placentas from term and preterm pregnancies complicated by intrauterine fetal death (IUFD).Study design. A retrospective cohort study was conducted including deliveries complicated by IUFD. A comparison was made between placentas from term and preterm (<37 weeks' gestation) pregnancies complicated by IUFD. A second analysis was undertaken comparing IUFD placentas delivered before and after 34 weeks' gestation. Uteroplacental insufficiency was defined when one or more of the following pathological features were found: placental infarct, poor vascularity of the chorionic villi, intravascular thrombi and vascular occlusion.Results. During the study period, 849 placentas of IUFD were examined. Gross and microscopic pathological finding were noted. When comparing gross and microscopic findings in term and preterm (<37 weeks) IUFD placentas, higher rates of calcifications, tissue congestion and cellular metaplasia were found in term vs. preterm placentas. Significantly increased rates of poor tissue vascularity, placental vascular occlusion and uteroplacental insufficiency were demonstrated in preterm IUFD placentas. When comparing pathological findings in IUFD placentas delivered before and after 34 weeks' gestation, higher rates of abnormal cord insertion, calcifications, tissue congestion, infarcts and intravascular thrombi as well as poor tissue vascularity and placental vascular occlusion were demonstrated in IUFD placentas delivered before 34 weeks. Regardless of gestational age at the time of IUFD in more than 90% of placentas vascular wall thickening was found. A third of both term and preterm placentas demonstrated histological chorioamionitis.Conclusions. A vast majority of IUFD placentas reveal numerous pathological findings that reflect uteroplacental insufficiency and abnormal blood supply. Different characteristics were noted in term and preterm placentas of pregnancies complicated by IUFD. Better definition of causes and associated placental pathological findings of IUFD might aid clinicians in counseling such patients regarding the reason and risk of recurrence in subsequent pregnancies.

Inhibition of mTOR attenuates store-operated Ca2+ entry in cells from endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension

Pulmonary vascular remodeling occurs in patients with chronic thromboembolic pulmonary hypertension (CTEPH). One factor contributing to this vascular wall thickening is the proliferation of pulmonary artery smooth muscle cells (PASMC). Store-operated Ca(2+) entry (SOCE) and cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) in PASMC are known to be important in cell proliferation and vascular remodeling in pulmonary hypertension. Rapamycin is widely known for its antiproliferative effects in injured coronary arteries. Although several reports have suggested favorable effects of rapamycin in animal models of pulmonary hypertension, no reports have been published to date in human tissues. Here we report that rapamycin has an inhibitory effect on SOCE and an antiproliferative effect on PASMC derived from endarterectomized tissues of CTEPH patients. Cells were isolated from endarterectomized tissues obtained from patients undergoing pulmonary thromboendarterectomy (PTE). Immunohistochemical analysis indicated high deposition of platelet-derived growth factor (PDGF) in tissue sections from PTE tissues and increased PDGF receptor expression. PDGF transiently phosphorylated Akt, mammalian target of rapamycin (mTOR), and p70S6 kinase in CTEPH cells from CTEPH patients. Acute treatment (30 min) with rapamycin (10 nM) slightly increased cyclopiazonic acid (10 microM)-induced Ca(2+) mobilization and significantly reduced SOCE. Chronic treatment (24 h) with rapamycin reduced Ca(2+) mobilization and markedly inhibited SOCE. The inhibitory effects of rapamycin on SOCE were less prominent in control cells. Rapamycin also significantly reduced PDGF-stimulated cell proliferation. In conclusion, the data from this study indicate the importance of the mTOR pathway in the development of pulmonary vascular remodeling in CTEPH and suggest a potential therapeutic benefit of rapamycin (or inhibition of mTOR) in these patients.

Significance of HLA Nondependent Risk Factors of Chronic Transplant Nephropathy for the Development of Endothelial Dysfunction After Kidney Transplantation

More than 40% of renal allografts show chronic transplant nephropathy (CTN) early after renal transplantation. Cardiovascular disease is the leading cause of death in this population. Thus endothelial dysfunction represents an early angiopathy causing CTN and atherosclerosis. We sought to evaluate changes in endothelial dysfunction and vascular wall thickness during the first year posttransplantation as well as their association with HLA nondependent risk factors for CTN. At 3 and 52 weeks after grafting, we studied 25 patients without overt atherosclerotic disease and acute posttransplant complications for von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), big endothelin-1 (ET-1), flow-mediated dilatation (FMD), intimal media thickness (IMT), serum total cholesterol (TC), and triglycerides (TAG). FMD and IMT at 52 weeks showed significant correlations ( P < .05) with recipient age, and the FMD ratios at 3 and 52 weeks correlated with the time on hemodialysis. Recipient age was significantly correlated with TC and PAI-1 with TAG. vWF was the only parameter that significantly correlated with donor age. There were no significant correlations with creatinine clearance. Decreased TAG approached statistical significance ( P = .07) and TC decreased nonsignificantly. The worsening of FMD and ET-1 was not significant. A nonsignificant improvement in IMT was not associated with any analyzed parameters. Our results implied that the time on hemodialysis, the presence of hyperlipoproteinemia, and the recipient age significantly contributed to endothelial dysfunction during the first year after transplantation.

Role of Phosphodiesterase 1A in Cold‐induced Hypertension and Cardiac Hypertrophy

The calcium/calmodulin‐dependent phosphodiesterase 1A (PDE1A) hydrolyzes the intracellular second messengers cAMP and cGMP. Cold exposure to (6 hr/day) results in hypertension and cardiac hypertrophy. PDE1A expression was up‐regulated in resistance arteries, kidneys and hearts of cold‐exposed rats. We hypothesized that RNAi inhibition of PDE1A would attenuate cold‐induced hypertension (CIH) and cardiac hypertrophy (CICH).We constructed AAV carrying PDE1AshRNA, ControlshRNA, and LacZ driven by a CMV promoter. Four groups received an intravenous injection of AAV.PDE1A‐shRNA, AAV.Control‐shRNA, AAV.LacZ, and PBS, respectively, before exposure to cold (5°C), while 1 group received PBS and was kept at room temperature as a control. BP was increased significantly in all cold‐exposed groups except the group treated with PDE1AshRNA, indicating that PDE1AshRNA prevented CIH. PDE1AshRNA enhanced hypothesive responses to acetylcholine in cold‐exposed rats, indicating improved endothelial dysfunction. The in vivo left ventricle wall thickness was also decreased significantly in the cold‐exposed rats treated with PDE1AshRNA. PDE1A‐shRNA attenuated the cold‐induced increases in heart weight, cardiomyocyte sizes, and vascular wall thickness. PDE1AshRNA increased intracellular cGMP and cAMP levels and decreased VSMC cell proliferation and migration. Thus, PDE1A plays a critical role in the pathogenesis of CIH and CICH.

Is 18F‐fluorodeoxyglucose positron emission tomography scanning a reliable way to assess disease activity in takayasu arteritis?

(18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning has been proposed as a new way of assessing disease activity in Takayasu arteritis (TA), but previous studies have used the nonvalidated National Institutes of Health (NIH) global activity criteria, and thus might be biased. This study was undertaken to determine the value of PET scanning for assessment of disease activity in TA, by comparing PET scan data with clinical, biologic, and magnetic resonance imaging (MRI) data assessed separately. Twenty-eight patients with TA (according to the American College of Rheumatology criteria) underwent a total of 40 PET scans. Images were reviewed by 2 pairs of independent nuclear medicine physicians and assessed for pattern and intensity of vascular uptake. TA activity data were obtained within 15 days of the PET scans. PET scanning revealed abnormal vascular uptake in 47% of the 40 examinations. The uptake intensity grade was 0 in 7 scans, grade 1 in 7 scans, grade 2 in 13 scans, and grade 3 in 13 scans. Morphologic analysis was conducted by grading the pattern of the vascular uptake as diffuse (73%), segmental (20%), or focal (13%). There was a trend toward an association between clinically active disease and the semiquantitative assessment of FDG uptake (P = 0.08). We found no statistical association between levels of acute-phase reactants and intensity of uptake. There was no significant association between the semiquantitative assessment of FDG uptake and the presence of vascular wall thickening (P = 0.23), gadolinium uptake (P = 0.73), or the presence of vascular wall edema (P = 0.56). Our findings indicate that there is no association between FDG vascular uptake intensity and clinical, biologic, or MRI assessment of disease activity. Previous studies using the nonvalidated NIH global activity criteria are likely biased.

Risk of cerebrovascular events after neck and supraclavicular radiotherapy: A systematic review

Objective Although low dose radiation therapy (RT) has been used to prevent re-occlusion of coronary arteries, it may also precipitate vascular damage. Specifically, irradiation to the neck is related to subsequent vascular wall thickening and atherosclerotic plaque formation. Several investigators, reporting patients with varied disease processes and using different methods, have described an increased risk of cerebrovascular events (CVEs) after RT to the neck for head and neck cancer, breast cancer, or lymphoma. Our purpose is to determine the rate and risk of CVEs in patients after receiving radiation therapy to the neck. Methods We performed a pooled analysis of the published data to document the cumulative risk of subsequent stroke after RT to the neck. An extensive MEDLINE and PUBMED search yielded five articles involving 6908 patients describing institutional series or cohort analyses comparing the frequency of CVE in irradiated versus non-irradiated patients. Results Sixty-six CVEs were reported in 2567 patients after neck RT, whereas only 12 CVEs were documented in 4119 non-irradiated patients. Crude risk of CVEs after neck RT was 2.6%, and was 0.29% in non-irradiated patients. This odds ratio of 9.0 was statistically significant (95% CI 4.9, 16.7; p < 0.0001). Data for supraclavicular RT were more difficult to analyze given differences in populations and reporting between the three studies, but it appears a significant risk is unlikely. Conclusions Neck RT increases the likelihood of CVEs, but this risk must be reconciled with the benefits of the therapy in the specific clinical situation. For instance, consideration should be made to limiting neck RT where possible for breast cancer and lymphoma patients.

Effect of Dietary Alpha-Linolenic Acid on Vascular Reactivity in Aorta of Spontaneously Hypertensive Rats

Several studies of hypertension have shown that dietary alpha-linolenic acid (ALA) has a blood pressure-lowering effect. In the present study, we investigated the effect of dietary ALA on endothelium-dependent vascular reactivity in six-week-old spontaneously hypertensive rats (SHR). At the end of the feeding period, systolic blood pressure in the ALA group was significantly lower than in the control group. There was no significant difference in endothelium-dependent vasorelaxant response between the two diet groups. There was also no significant inter-group difference in the vascular wall thickness and media-to-lumen ratio. In conclusion, the present findings suggest that the blood pressure-lowering mechanism of dietary ALA does not involve increased sensitivity to NO or a change the in vascular morphology of the aorta.

Increased carotid intima-media thickness in patients with pheochromocytoma in comparison to essential hypertension

Catecholamines due to various mechanisms may contribute to the accumulation of collagen fibers and extracellular matrix in the arterial wall. The aim of this study was to compare intima-media thickness (IMT) of the common carotid artery (CCA) and carotid bifurcation (CB) in patients with pheochromocytoma, essential hypertension and healthy controls. Carotid ultrasound studies were carried out in 30 patients with pheochromocytoma matched for age and gender with 80 patients with essential hypertension and 40 normotensive controls. Significantly higher IMT was found in patients with pheochromocytoma and essential hypertension compared to controls when measured in the CCA (0.931+/-0.223, 0.825+/-0.146 and 0.738+/-0.113 mm; P<0.001; P<0.05), and only in patients with pheochromocytoma compared to controls in the region of CB (1.359+/-0.593, 1.095+/-0.311 and 0.968+/-0.247 mm; P<0.001; P=0.13). Higher IMT in patients with pheochromocytoma compared to patients with essential hypertension was also statistically significant in both carotid regions (both P<0.01). This difference remained significant after adjustment for all relevant clinical and biochemical covariates in the CCA (P=0.014) but disappeared in the region of CB (P=0.079). In summary, patients with pheochromocytoma have increased common carotid IMT when compared to patients with essential hypertension. This finding could be caused by the deleterious effects of the excess of catecholamines on the vascular wall growth and thickening.

Abstract 324: RNAi Inhibition of Phosphodiesterase 1A Prevents Cold-Induced Hypertension and Cardiac Hypertrophy

The calcium/calmodulin-dependent phosphodiesterase 1A (PDE1A) hydrolyzes the intracellular second messengers cAMP and cGMP, which are known to play an important role in regulating vascular tone and smooth muscle cell (VSMC) proliferation. Intermittent exposure to cold (6 hr/day) results in hypertension and cardiac hypertrophy. Interestingly, PDE1A expression was up-regulated in resistance arteries, kidneys and heart of rats exposed to cold. We hypothesize that RNAi inhibition of PDE1A would attenuate cold-induced hypertension (CIH) and cardiac hypertrophy (CICH). We constructed PDE1A shRNA (PDE1A-shRNA) plasmid, Control-shRNA plasmid, and LacZ plasmid driven by a CMV promoter. AAV-2 was used for in vivo gene delivery. Five groups of rats were used to test the effect of in vivo inhibition of PDE1A expression on the development of CIH and CICH. Four groups received an intravenous injection of AAV.PDE1A-shRNA, AAV.Control-shRNA, AAV.LacZ, and PBS, respectively, before intermittent exposure to moderate cold temperature (5°C), while the last group received PBS and was kept at room temperature (25°C) as a control. Blood pressure (BP), monitored using a telemetry system, was increased significantly in all cold-exposed groups except the group treated with PDE1A-shRNA, indicating that PDE1A-shRNA prevented the development of CIH. PDE1A-shRNA enhanced hypothesive responses to acetylcholine in cold-exposed rats, indicating improved endothelial dysfunction. The MRI analysis indicated that the in vivo left ventricle wall thickness was also decreased significantly in the cold-exposed rats treated with PDE1A-shRNA. All animals were sacrificed at 10 weeks after gene delivery. PDE1A-shRNA significantly attenuated the cold-induced increases in heart weight, cardiomyocyte sizes, and vascular wall thickness. PDE1A-shRNA increased intracellular cGMP and cAMP levels and decreased VSMC cell proliferation and migration. PDE1A protein expression was significantly decreased, indicating effective silence of PDE1A gene. RNAi inhibition prevented CIH, CICH and cold-induced vascular dysfunction and hypertrophy. Thus, PDE1A plays a critical role in the pathogenesis of CIH and CICH.

Prednisolone inhibits PDGF-induced nuclear translocation of NF-kappaB in human pulmonary artery smooth muscle cells.

Pulmonary vascular remodeling, a major cause for the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH), is partially due to increased proliferation of pulmonary arterial smooth muscle cells (PASMC) in the media, resulting in vascular wall thickening. Platelet-derived growth factor (PDGF) is a potent mitogen that may be involved in the progression of PAH. Blockade of PDGF receptors has been demonstrated to have therapeutic potential for patients with severe pulmonary hypertension. Prednisolone is an immunosuppressant shown to have anti-inflammatory and antiproliferative effects on PASMC. This study was designed to investigate whether PDGF and prednisolone affect human PASMC proliferation by regulating the nuclear translocation of NF-kappaB (a transcription factor composed of 2 subunits, p50 and p65). Treatment of human PASMC with PDGF (10 ng/ml) significantly increased nuclear translocation of p50 and p65 subunits. Inhibition of NF-kappaB activation or nuclear translocation of p50/p65 significantly attenuated PDGF-induced PASMC proliferation (determined by [(3)H]thymidine incorporation). In the presence of prednisolone (200 microM), the PDGF-induced nuclear translocation of p50 and p65 subunits was markedly inhibited (P < 0.05 vs. the cells treated with PDGF alone). These results indicate that PDGF-induced nuclear translocation of NF-kappaB may play an important role in stimulating PASMC proliferation (and/or enhancing PASMC survival), whereas prednisolone may exert anti-inflammatory and antiproliferative effects on PASMC by inhibiting NF-kappaB nuclear translocation.

Activation of cytosolic phospholipase A2 and fatty acid transacylase is essential but not sufficient for thrombin-induced smooth muscle cell proliferation

Thrombin is a potent stimulant of smooth muscle cell (SMC) proliferation in inflammatory conditions, leading to pathological thickening of vascular walls in atherosclerosis and airway remodeling in asthma. Cell proliferation requires the formation and remodeling of cell membrane phospholipids (PLs), involving the activation of PL-metabolizing enzymes. Yet, the role of specific PL-metabolizing enzymes in SMC proliferation has hardly been studied. To bridge this gap, in the present study, we investigated the role of key enzymes involved in PL metabolism, the PL-hydrolyzing enzyme phospholipase A2 (PLA2) and the PL-synthesizing enzyme lysophosphatidic acid-fatty acid transacylase (LPAAT), in thrombin-induced proliferation of bovine aortic SMCs (BASMCs). Concomitantly with the induction of BASMC proliferation, thrombin activated cytosolic PLA2 (cPLA2-alpha), expressed by selective release of arachidonic acid and mRNA expression, as well as LPAAT, expressed by nonselective incorporation of fatty acid and mRNA expression. Specific inhibitors of these enzymes, arachidonyl-trifluoromethyl-ketone for cPLA2 and thimerosal for LPAAT, suppressed their activities, concomitantly with suppression of BASMC proliferation, suggesting a mandatory requirement for cPLA2 and LPAAT activation in thrombin-induced SMC proliferation. Thrombin acts through the protease-activated receptor (PAR-1), and, accordingly, we found that thrombin-induced BASMC proliferation was suppressed by the PAR-1 inhibitor SCH-79797. However, the PAR-1 inhibitor did not prevent thrombin-induced mRNA expression of cPLA2 and LPAAT, implying that the activation of cPLA2 and LPAAT is essential but not sufficient for thrombin-induced proliferation of BASMCs.

Cilostazol alleviates cerebral small-vessel pathology and white-matter lesions in stroke-prone spontaneously hypertensive rats

Small-vessel pathology is believed to have a critical role in cerebrovascular white-matter (WM) lesions. However, the cellular aspect of vascular pathology, including the phenotypic modulation of smooth-muscle cells (SMCs) and its role in the small-vessel disease, remains undefined. The involvement or otherwise of the phenotypic modulation of SMCs in cerebral small-vessel pathology has been investigated, and the effect of cilostazol on both the small vessels and the WM lesions has been determined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP and Wistar Kyoto rats were used. SHRSP were divided into two groups: the cilostazol-treated (20-week treatment) and vehicle-treated groups. Small-vessel pathology was analyzed using both histopathology and immunohistochemistry for smooth-muscle actin and nonmuscle myosin heavy chain (SMemb, a marker for the synthetic phenotype of SMC). The pathological changes in the WM were quantified in terms of the numerical density of activated microglia and the degree of WM lesions. Vascular wall thickening and perivascular fibrosis, determined by the wall area/lumen area ratio and the collagen area/total vessel area ratio, respectively, showed an increase in the vehicle-treated SHRSP, and this increase was significantly attenuated by cilostazol treatment. The percentage of small vessels immunopositive for SMemb was also reduced by cilostazol treatment. In the cilostazol-treated SHRSP, microglial activation and the degree of WM lesions were attenuated compared with the vehicle-treated SHRSP. The results indicated that cilostazol attenuates the phenotypic modulation of SMC associated with cerebral small-vessel pathology and WM lesions without causing changes in the blood pressure.

Role of the Angiotensin II Type 2 Receptor in Arterial Remodeling after Wire Injury in Mice

The angiotensin II type 2 (AT2) receptor promotes apoptosis and inhibits cell proliferation. In the present study, we investigated the role of the AT2 receptor in vascular repair and remodeling following severe vascular injury using AT2 knockout (AT2KO) mice. Left femoral arteries of AT2KO mice and wild-type (WT) control mice were injured by a 0.38 mm steel wire inserted from the lumen. Twenty-eight days after the injury, a concentric vascular wall thickening, composed largely of neointima, was noted both in AT2KO and WT mice. The area occupied by the neointima and the cell count within it were not different in the two mouse strains. However, the area of the medial layer and the cell count within it were significantly larger in AT2KO mice than in WT mice. A BrdU incorporation assay showed that the proliferative activity was high in the neointima but it was not different between the strains. On the other hand, apoptosis assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) was significantly inhibited in the neointima and the media of AT2KO mice compared to the levels in WT mice. However, the number of TUNEL-positive cell was much smaller in the neointima than in the medial layer in both strains. Taken together, these results indicate that AT2 receptors promote the apoptosis of vascular cells but have no net effect on the neointimal cell growth or luminal narrowing after wire injury. The AT2 receptor may be involved in the control of medial layer thickness, at least in part, through medial cell apoptosis.

Caracterização morfoanatômica do colmo de híbridos de milho para avaliar a qualidade de silagem

The objective was to evaluate morphoanatomical characteristics and possible correlations with cell wall digestibility and with lignin of ten corn hybrids (DK265bm3, DK265, HS5, HS6, HTV2, HTV27, Anjou285, Mexxal, Pistachio and Buxxil) planted at INRA (Unité of Génétique Amélioration des Plant Fourragères, Lusignan, France) in 150 m² areas. A completely randomized experimental design with five replications was used. With exception for cortical length, significant differences were verified as for the evaluated morphoanatomical aspects, with hybrid DK265bm3 being characterized by lower counts of lignified cells in the medullar parenchyma and cortical areas, lower percentage of medullar parenchyma and higher percentage of cortex in relation to other hybrids. However, DK265bm3 did not differ from other hybrids in regards to vascular bundle surface and cell wall thickness of the vascular bundle. Using correlation analysis a positive correlation was observed between the levels of Klason lignin and lignin in acid detergent with the number of lignified cells in the parenchyma and cortex. IVCNDF showed a negative correlation with the proportion of lignified cells in medullar parenchyma and lignified cells in the cortex.

Hypertension and Hypercholesterolemia Differentially Affect the Function and Structure of Pig Carotid Artery

The purpose of this work was to compare the effects of hypertension and hypercholesterolemia on carotid endothelial function, structure, and vasa vasorum density. Seventeen pigs were randomized to a 12-week normal diet without (n=5), or with renovascular hypertension (HT; n=6), or to a high cholesterol diet (HC; n=6). Carotid arteries were studied by organ chambers (endothelial function) and microcomputed tomography (vasa vasorum), and tissue was processed for Sirius red staining and immunoblotting (vascular endothelium growth factor, endostatin, matrix metalloproteinase-9, and matrix metalloproteinase-2). HC and HT showed reduced vasodilation to acetylcholine as compared with controls, but HT also had a lower response to sodium nitroprusside. In addition, HT showed a higher content of organized collagen fibers and increased intima-media thickness. Vasa vasorum density was increased in HC but not in HT. Both HT and HC showed a proangiogenetic biochemical milieu (higher vascular endothelium growth factor, matrix metalloproteinases, and lower endostatin), but this was more pronounced in HC. Both hypertension and hypercholesterolemia induce endothelial dysfunction in the carotid artery. However, hypertension is also associated with greater fibrosis and vascular wall thickening, which might impair endothelium-independent vasorelaxation and vasa vasorum growth. Hypercholesterolemia is, in turn, associated with vasa vasorum neovascularization. These data suggest that carotid atherosclerosis can evolve through different mechanisms in relation to different risk factors.

Abstract 668: Inhibition of DNA Methyltransferase Inhibits the Ang II-Induced Increase in Blood Pressure, Vascular Remodeling and Target Organ Damage

Growth signals stimulate DNA methyltransferase (DNMT) expression through extracellular signal-regulated kinases 1/2 (ERK1/2) pathway and that inhibition of ERK1/2 signaling results in repression of DNMT expression and activation of expression of some DNMT-repressed genes. Angiotensin II (Ang II) has been shown to stimulate ERK1/2 signaling in resistance arteries. We hypothesized that Ang II stimulates DNMT expression resulting in methylation and repression of antihypertensive genes such as 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) and that blocking DNMT activity may inhibit Ang II-induced hypertension, vascular remodeling, and target organ damage. C57BL/6J (C57) mice were treated with the specific DNMT inhibitor 5′-aza-2′-deoxycytidine (aza-CdR, 1 mg/kg/day) intraperitoneally for 3 consecutive days before subcutaneous Ang II infusion for 28d at a pressure dose of 0.7 mg/kg/day using Alzet osmotic minipumps. Systolic blood pressure was monitored during this period and tissues were harvested to determine vascular wall thickness, cardiac hypertrophy, and expression and methylation of 11β-HSD2 in arteries and the kidneys. Ang II infusion induced a more than 2-fold increase in DNMT1 expression (n=6, p≤ 0.05). Moreover, blocking DNMT1 activity significantly inhibited the Ang II-induced increase in systolic and diastolic blood pressure (from 102 ± 3 to138 ± 7 for saline-treated vs. 101 ± 4 to 105 ± 6 mm Hg for aza-CdR-treated mice, n=8, p≤ 0.01 for saline vs.aza-CdR in the presence of Ang II treatment). In addition, expression of 11β-HSD2 was inhibited by Ang II treatment. However, expression of 11β-HSD2 was found to be above the background observed in absence of Ang II when Ang II treatment was associated with DNMT activity blockade. Methylation-specific PCR indicated that 11β-HSD2 was methylated in the arteries and kidneys but its Ang II-dependency is still to be determined. Finally when DNMT activity was inhibited, the Ang II-induced increase cardiac hypertrophy (heart/body weight) and wall/lumen ratio in the carotid arteries were significantly inhibited (n= 8, p≤ 0.05). These results suggest that DNA methylation plays a critical role in the coordinate regulation of genes involved in the pathogenesis of hypertension and vascular remodeling.

Adult-onset calorie restriction delays the accumulation of mitochondrial enzyme abnormalities in aging rat kidney tubular epithelial cells

Adult-onset calorie restriction (A-CR) is an experimental model of life extension and healthy aging less explored, compared with calorie restriction begun at early ages, but one more realistic for human application. We examined the effect of A-CR on the aging rat kidney with respect to common structural age-dependent changes and the accumulation of mitochondrial enzyme abnormalities in tubular epithelial cells. A 40% calorie restriction was initiated in middle-aged rats, before the onset of significant age-related changes in the Fischer x Brown Norway rat kidney. This dietary intervention effectively reduced glomerulosclerosis and tubular atrophy within 6 mo and changed the rate of interstitial fibrosis formation within 1 yr and vascular wall thickening and the expression cytochrome c oxidase (COX)-deficient tubular epithelial cells in 18 mo compared with age-matched ad libitum-fed rats. Our histological approach (histochemical staining for mitochondrial enzyme activity and laser capture microdissection) coupled with mitochondrial DNA (mtDNA) PCR analyses demonstrated that COX-deficient renal tubular epithelial cells accumulated mtDNA deletion mutations and that these cells contained unique, clonally expanded mtDNA deletion mutations. Renal tubular epithelial cells with mitochondrial abnormalities presented cellular characteristics indicative of physiological dysfunction.

Noninvasive Assessment of Pulmonary Arterial Capacitance by Echocardiography

Pulmonary arterial capacitance (PAC) has been associated with right ventricular (RV) workload and mortality in pulmonary hypertension, but is not routinely evaluated in children. We investigated whether PAC can be estimated noninvasively by echocardiography. We retrospectively determined PAC in 31 children with pulmonary hypertension, using echocardiography, and compared the results with those obtained at cardiac catheterization. PAC derived from echocardiography was similar to that derived from catheterization (mean +/- SD 1.16 +/- 1.0 vs 1.10 +/- 0.95 mL(3) x mm Hg(-1), P = not significant) and the two correlated well (r = 0.74, P < .0001). There was a highly significant polynomial relationship between PAC and RV anterior wall thickness indexed to body surface area (R(2) = 0.54, P < .0001), but not between pulmonary vascular resistance and RV wall thickness. Pulmonary vascular resistance and PAC did not correlate. Echocardiography can reliably estimate PAC, which strongly correlates with RV hypertrophy, a surrogate for RV work.

Dépistage de l'atteinte aortique abdominale par échographie-doppler au diagnostic de maladie de Horton. Étude prospective de 30 patients

Inflammatory involvement of extracranial large-sized arteries occurs in 10-20% of patients with giant cell (temporal) arteritis. Aortic involvement may reveal giant cell arteritis or occur as a late-onset complication, and represents one of the most serious manifestation of the disease with the risk of aortic dissection and/or aneurysm rupture. The thoracic aorta is more frequently involved but abdominal aortitis may also occur in giant cell arteritis. To date, few data are available about abdominal aorta changes at the initial stage of giant cell arteritis. This prospective monocentric study was conducted between May 1998 and May 2002, and included 30 consecutive patients with biopsy-proven giant cell arteritis. Standard clinical and biological data were collected. Each patient underwent an abdominal aortic Doppler-sonography that looked for aneurysm, ectasia, thickening of the vascular wall, and hypoechoic halo around the aorta. Among the 30 patients of this study (25 women, 5 men, mean age 68.5 years), 4 (13%) had an abdominal aortic aneurysm, with a low diameter (23 to 27 mm), measuring 2 to 5.5 cm in length. A vascular wall thickening superior or equal to 3 mm was noted in 17 patients (68%). A 4 to 8 mm periaortic hypoechoic halo was found in 10 patients (33%). This halo was present in 3 out of the 4 patients with aneurysm. Aortic involvement is a potentially serious complication of giant cell arteritis. The question of a systematic screening of this complication remains open to discussion. Our study shows that Doppler sonography may detect morphological abnormalities on the abdominal aorta at the initial stage of giant cell arteritis. These abnormalities comprise mild aneurysms, thickening of the vascular wall and periaortic halo, which could correspond to inflammatory locations of the disease. Complementary studies are needed to assess their specificity and their seriousness.