Atrophic remodeling of the artery-cuffed artery.
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Increased arterial wall tension stimulates growth and remodeling of arteries, but little is known about the effects of decreased wall tension, despite its developmental and pathological significance. Consequently, we cuffed 1 carotid artery in rabbits with a portion of the contralateral artery to off-load circumferential wall tension. The model produced rapid and extensive atrophy of the cuffed artery that yielded decreases in the DNA content of the cuffed artery (a measure of cell number) from 8.0+/-0.5 microgram/cm of in situ vessel length to 5.6+/-0.5 microgram/cm at 21 days postoperatively. The elastin content of the cuffed artery was also significantly reduced, from 399+/-17 to 283+/-17 microgram/cm, and collagen content was reduced from 468.0+/-59.0 to 154+/-24 microgram/cm (P<0.05) at 21 days postoperatively. Detection of DNA oligonucleosomes by gel electrophoresis implicated apoptotic cell death in remodeling due to cuffing. Upregulation of matrix metalloproteinases (MMPs), including MMP-2, MMP-9, and unidentified gelatinases, indicated that these enzymes may also be involved in remodeling. No further changes in wall structure were seen between 3 weeks and 6 months, and the excised artery that was used as a cuff exhibited normal medial morphology for at least 6 months postoperatively. We infer from these experiments that off-loading of arterial wall tension induces rapid and extensive atrophy of the arterial media. (+info)
Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice.
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Apolipoprotein E-deficient (ApoE-/-) mice develop atherosclerotic lesions throughout the arterial tree, including the carotid bifurcation. Although the expression of adhesion molecules such as ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and P-selectin on endothelium that overlie atherosclerotic plaques has been implicated in monocyte recruitment to developing lesions, monocyte adhesion in atherosclerotic vessels has not been observed directly. To investigate which adhesion molecules may be important in monocyte adhesion to atherosclerotic lesions, an isolated mouse carotid artery preparation was developed and perfused with mononuclear cells. We show rolling and attachment of the human monocytic cell line U937 and the mouse monocyte-macrophage cell line P388D1 in carotid arteries from 10- to 12-week-old ApoE-/- and C57BL/6 wild-type mice fed a Western-type diet (21% fat wt/wt) for 4 to 5 weeks. No rolling was observed in carotid arteries from C57BL/6 or BALB/c wild-type mice fed a chow diet and little was observed in BALB/c mice fed a Western-type diet. This model represents early lesion development as shown by minimal macrophage infiltration in the intima of carotid arteries from ApoE-/- mice fed a Western-type diet. Rolling was observed at shear stresses that were characteristic of the low-shear recirculation zone near the carotid bifurcation. Mononuclear cell attachment and rolling were significantly inhibited by monoclonal antibody blockade of P-selectin or its leukocyte ligand P-selectin glycoprotein ligand-1. Rolling velocities increased after monoclonal antibody blockade of mononuclear cell alpha4-integrin or VCAM-1, which indicates that alpha4-integrin interacting with VCAM-1 stabilizes rolling interactions and prolongs monocyte transit times. (+info)
Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits.
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BACKGROUND: Hypercholesterolemia reduces nitric oxide bioavailability, manifested by reduced endothelium-dependent vascular relaxation, and also induces vascular adhesion molecule expression and inflammatory cell infiltration. We have previously shown that gene therapy with NO synthase in hypercholesterolemic rabbits substantially reverses the deficit in vascular relaxation. In the present study, we show that NO synthase gene therapy rapidly and substantially reduces vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration. METHODS AND RESULTS: Thirty male New Zealand White rabbits were maintained on a 1% cholesterol diet for 11 to 13 weeks, then underwent carotid artery gene transfer with Ad.nNOS or Ad.betaGal (recombinant adenoviruses expressing neuronal NO synthase or beta-galactosidase, respectively), or received medium alone in a sham procedure. Arteries were harvested at 1 and 3 days after gene transfer, and the following parameters were determined by immunohistochemical and image-analysis techniques: intercellular adhesion molecule-1, vascular cell adhesion molecule-1, lipid deposition by oil red O staining, lymphocyte infiltration (CD43-positive cells), and monocyte infiltration (RAM-11-positive cells). In Ad.nNOS-treated arteries, all markers were significantly decreased relative to Ad. betaGal or sham-treated arteries within 3 days after gene transfer. Ad.nNOS had a particularly striking impact on monocyte infiltration; as early as 24 hours after gene transfer, Ad.nNOS-treated arteries had >3-fold fewer monocytes than Ad.betaGal- or sham-treated arteries. CONCLUSIONS: NO synthase gene therapy rapidly ameliorates several markers of atherosclerosis in the cholesterol-fed rabbit. (+info)
Plasminogen activator inhibitor-1 is a major determinant of arterial thrombolysis resistance.
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BACKGROUND: Platelet-rich thrombi are resistant to lysis by tissue plasminogen activator (tPA). Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of tPA, may contribute to arterial thrombolysis resistance. However, few data are available regarding the effect of PAI-1 on arterial thrombolysis in animals. We used a murine carotid injury model to test the hypothesis that PAI-1 inhibits thrombolysis mediated by pharmacological concentrations of tPA. METHODS AND RESULTS: Platelet-rich thrombi were induced in wild-type mice (PAI-1 +/+; n=11) and PAI-1-deficient mice (PAI-1 -/-; n=11) with ferric chloride. Baseline carotid blood flows and mean occlusion times did not differ between PAI-1 +/+ and PAI-1 -/- mice. Clot lysis was induced by infusion of heparin (200 U/kg bolus, 70 U. kg-1. h-1 drip), human plasminogen (50 mg/kg), and tPA at 20 (n=10) or 100 (n=12) microg. kg-1. min-1. Mean plasma tPA antigens were 2.7 microg/mL (tPA infusion, 20 microg. kg-1. min-1) and 5.5 microg/mL (tPA infusion, 100 microg. kg-1. min-1), with no significant differences between PAI-1 +/+ mice and PAI-1 -/- mice. Reperfusion after tPA 20 microg. kg-1. min-1 occurred in 1 of 5 PAI-1 +/+ mice versus 5 of 5 PAI-1 -/- mice (P=0.0006). Reperfusion occurred in all mice that received tPA 100 microg. kg-1. min-1, but reperfusion times were significantly shorter in PAI-1 -/- mice (17. 8+/-2.6 minutes, n=6) than in PAI-1 +/+ mice (35.7+/-5.1 minute, n=6; P=0.01). Histological analyses confirmed that carotid thrombi were platelet rich and that PAI-1 was distributed uniformly throughout thrombi from PAI-1 +/+ mice. Lysates of PAI-1 +/+ platelets inhibited human tPA, whereas PAI-1 -/- platelet lysates did not. CONCLUSIONS: PAI-1 is a major determinant of the resistance of platelet-rich arterial thrombi to lysis by pharmacological concentrations of tPA. Strategies to inhibit or resist PAI-1 may enhance thrombolysis. (+info)
Potassium ions and endothelium-derived hyperpolarizing factor in guinea-pig carotid and porcine coronary arteries.
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Experiments were designed to determine in two arteries (the guinea-pig carotid and the porcine coronary arteries) whether or not the endothelium-derived hyperpolarizing factor (EDHF) can be identified as potassium ions, and to determine whether or not the inwardly rectifying potassium current and the Na+/K+ pump are involved in the hyperpolarization mediated by EDHF. The membrane potential of vascular smooth muscle cells was recorded with intracellular microelectrodes in the presence of N(omega)-L-nitro-arginine (L-NA) and indomethacin. In vascular smooth muscle cells of guinea-pig carotid and porcine coronary arteries, acetylcholine and bradykinin induced endothelium-dependent hyperpolarizations (-18+/-1 mV, n = 39 and -19+/-1 mV, n = 7, respectively). The hyperpolarizations were not affected significantly by ouabain (1 microM), barium chloride (up to 100 microM) or the combination of ouabain plus barium. In both arteries, increasing extracellular potassium concentration by 5 or 10 mM induced either depolarization or in a very few cases small hyperpolarizations which never exceeded 2 mV. In isolated smooth muscle cells of the guinea-pig carotid artery, patch-clamp experiments shows that only 20% of the vascular smooth muscle cells expressed inwardly rectifying potassium channels. The current density recorded was low (0.5+/-0.1 pA pF(-1), n = 8). These results indicate that, in two different vascular preparations, barium sensitive-inwardly rectifying potassium conductance and the ouabain sensitive-Na+/K+ pump are not involved in the EDHF-mediated hyperpolarization. Furthermore, potassium did not mimic the effect of EDHF pointing out that potassium and EDHF are not the same entity in those arteries. (+info)
Muscular strength training is associated with low arterial compliance and high pulse pressure.
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Aerobic exercise training increases arterial compliance and reduces systolic blood pressure, but the effects of muscular strength training on arterial mechanical properties are unknown. We compared blood pressure, whole body arterial compliance, aortic impedance, aortic stiffness (measured by beta-index and carotid pulse pressure divided by normalized systolic expansion [Ep]), pulse wave velocity, and left ventricular parameters in 19 muscular strength-trained athletes (mean+/-SD age, 26+/-4 years) and 19 sedentary controls (26+/-5 years). Subjects were healthy, non-steroid-using, nonsmoking males, and athletes had been engaged in a strength-training program with no aerobic component for a minimum of 12 months. There was no difference in maximum oxygen consumption between groups, but handgrip strength (mean+/-SEM, 44+/-2 versus 56+/-2 kg; P<0.01) and left ventricular mass (168+/-8 versus 190+/-8 g; P<0.05) were greater in athletes. Arterial stiffness was higher in athletes, as evidenced by lower whole body arterial compliance (0.40+/-0.04 versus 0.54+/-0.04 arbitrary compliance units; P=0.01), higher aortic characteristic impedance (1.55+/-0.13 versus 1.18+/-0.08 mm Hg. s. cm-1; P<0.05), beta-index (4.6+/-0.2 versus 3.8+/-0.4; P<0. 05), and ln Ep (10.86+/-0.06 versus 10.60+/-0.08; P<0.01). Femoral-dorsalis pedis pulse wave velocity was also higher in the athletes, but carotid-femoral pulse wave velocity was not different. Furthermore, both carotid (56+/-3 versus 44+/-2 mm Hg; P<0.001) and brachial (60+/-3 versus 50+/-2 mm Hg; P<0.01) pulse pressures were higher in the athletes, but mean arterial pressure and resting heart rate did not differ between groups. These data indicate that both the proximal aorta and the leg arteries are stiffer in strength-trained individuals and contribute to a higher cardiac afterload. (+info)
Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions.
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BACKGROUND: Oxidized LDL (Ox-LDL) seems to play key roles in atherogenesis. Lectinlike Ox-LDL receptor-1 (LOX-1) is a recently identified cell-surface receptor for Ox-LDL. The relationship of this novel receptor for Ox-LDL to atherogenesis, however, has not yet been clarified. In this study, we explored the expression of LOX-1 in the atherosclerotic lesions of human carotid arteries. METHODS AND RESULTS: Using carotid endarterectomy specimens obtained from 21 patients and 2 samples of normal human aortas, we examined LOX-1 expression by reverse transcription-polymerase chain reaction and immunohistochemistry. In aortas without atherosclerosis, LOX-1 expression was undetectable by immunohistochemistry and negligible by reverse transcription-polymerase chain reaction. In carotid arteries, luminal endothelial cells covering early atherosclerotic lesions were more frequently positive for LOX-1 expression than those in advanced atherosclerotic lesions. Endothelial cells in the intimal neovasculature of advanced lesions also expressed LOX-1. In addition, macrophages and smooth muscle cells in the intima of advanced atherosclerotic plaques were positive for LOX-1 expression. CONCLUSIONS: LOX-1 may play important roles in Ox-LDL uptake and subsequent functional alteration in the luminal endothelium in early atherosclerotic lesions and in intimal neovascular endothelial cells in advanced plaques. Furthermore, LOX-1 may also be involved in Ox-LDL uptake and subsequent foam cell transformation in macrophages and smooth muscle cells in the atherosclerotic intima. (+info)
PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.
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BACKGROUND: Adhesion molecule expression on the endothelial cell (EC) surface is critical for leukocyte recruitment to atherosclerotic lesions. Better understanding of transcriptional regulation of adhesion molecules in ECs may provide important insight into plaque formation. Peroxisome proliferator-activated receptor-alpha (PPARalpha), a member of the nuclear receptor family, regulates gene expression in response to certain fatty acids and fibric acid derivatives. The present study investigated PPARalpha expression in human ECs and their regulation of vascular cell adhesion molecule-1 (VCAM-1). METHODS AND RESULTS: Immunohistochemistry revealed that human carotid artery ECs express PPARalpha. Pretreatment of cultured human ECs with the PPARalpha activators fenofibrate or WY14643 inhibited TNF-alpha-induced VCAM-1 in a time- and concentration-dependent manner, an effect not seen with PPARgamma activators. Both PPARalpha activators decreased cytokine-induced VCAM-1 mRNA expression without altering its mRNA half-life. Transient transfection of deletional VCAM-1 promoter constructs and electrophoretic mobility shift assays suggest that fenofibrate inhibits VCAM-1 transcription in part by inhibiting NF-kappaB. Finally, PPARalpha activators significantly reduced adhesion of U937 cells to cultured human ECs. CONCLUSIONS: Human ECs express PPARalpha, a potentially important regulator of atherogenesis through its transcriptional control of VCAM-1 gene expression. Such findings also have implications regarding the clinical use of lipid-lowering agents, like fibric acids, which can activate PPARalpha. (+info)