Establishment and ultrasound characteristics of atherosclerosis in rhesus monkey

Background

Atherosclerosis is one of the main risk factors cause acute cerebral-cardio vascular diseases. It's of great significance to establish an atherosclerosis animal model that can mimic the characteristics and nature course of human patients. Therefore, a rhesus monkey model was induced by high-fat diet to monitor their lipid profile and intima-media thickness (IMT) of artery walls and study atherosclerosis progression.

Methods

Fifty male rhesus monkeys were enrolled in this study. All of these monkeys were aged 7 to 14 years with BMI >30 kg/m². They were fed with high-fat diet containing 10% of fat for the first 48 weeks. Use ultrasound to measure the IMT at bilateral common carotid arteries and their bifurcations and aorta (AO) of the monkeys, and screen out the individuals with thickened IMT for the next phase. In the next 48 weeks, some of these monkeys (n = 4) were fed with standard diet containing 3% fat. Meanwhile the other monkeys (n = 5) were fed with high-fat diet for another 48 weeks. Their serum lipid level was monitored and arterial IMT was also determined periodically.

Results

Serum lipid level of all 50 monkeys elevated after fed with high-fat diet for the first 48 weeks. IMT thickening at right common carotid bifurcation and aorta (AO) was thickened in 9 monkeys. Furthermore, 4 of these 9 monkeys were fed with standard diet and other 5 monkeys were fed with high-fat diet in the following 48 weeks. The serum lipid level of the 4 monkeys recovered and their IMT at RBIF and AO did not progress. However, the lipid level of other 5 monkeys remained high, and their IMT thickening of AO progressed, and plaques and calcification focuses were found at the anterior wall of aorta near the bifurcation of common iliac artery.

Conclusions

After high-fat diet induction for 96 weeks, serum lipid levels of rhesus monkeys elevated significantly, which subsequently caused IMT thickening and plaques formation. When IMT thickening occurred, further vascular injury may be prevented by reducing diet fat content. Our study indicates that vascular injury of high-fat diet induced rhesus monkey is similar to that of human in position and progression.

     

Differences in vascular responses to vasoactive agents of basilar artery and aorta from rabbits with alloxan-induced diabetes.

Responses of the basilar artery and aorta to vasoactive agents in alloxan-induced diabetic and age-matched control rabbits were examined. There were no significant differences in the reactivity of the basilar artery to norepinephrine (NE), 5-hydroxytryptamine (5-HT), and K+ between age-matched control and diabetic rabbits. The maximal contraction of the aorta with endothelium in response to NE was significantly enhanced in the case of the aorta from diabetic rabbits. Pretreatment with 10(-6) M methylene blue or removal of the endothelium enhanced the contractile response of aorta to NE from control rabbits and, after such treatment, the concentration-response curve to NE was almost identical to that of aorta from diabetic rabbits. Basal levels of cyclic GMP but not cyclic AMP in the diabetic aorta with endothelium were significantly lower than those in the control aorta with endothelium. These results demonstrate that the cerebral artery is resistant to diabetes mellitus within 10 weeks as compared with the peripheral artery. The enhancement in the contractile response of aorta to NE in diabetic rabbits is due to the attenuation of the spontaneous release of endothelium-derived relaxing factor, through an impairment of the function of endothelial cells.     

The cerebral artery in cynomolgus monkeys (Macaca fascicularis)

Cerebral artery structure has not been extensively studied in primates. The aim of this study was to examine the cerebrovascular anatomy of cynomolgus monkeys (Macaca fascicularis), which are one of the most commonly used primates in medical research on human diseases, such as cerebral infarction and subarachnoid hemorrhage. In this study, we investigated the anatomy and diameter of cerebral arteries from 48 cynomolgus monkey brain specimens. We found three anatomical differences in the vascular structure of this species compared to that in humans. First, the distal anterior cerebral artery is single. Second, the pattern in which both the anterior inferior cerebellar artery and posterior inferior cerebellar artery branch from the basilar artery is the most common. Third, the basilar artery has the largest diameter among the major arteries. We expect that this anatomical information will aid in furthering research on cerebrovascular disease using cynomolgus monkeys.     

Suppression of high lipid diet induced by atherosclerosis sarpogrelate

Sarpogrelate (SP), a serotonin (5‐HT2A) receptor antagonist, is used as an anti‐platelet agent for the treatment of some vascular diseases. SP has been reported to inhibit 5‐HT induced coronary artery spasm, increase in intracellular calcium and smooth muscle cells proliferation. This study was undertaken to test that SP suppresses the development of atherosclerosis due to high cholesterol diet (HCD) by decreasing blood viscosity and oxidative stress. For this purpose, 29 rabbits were divided into four groups: control group (normal diet); normal diet group with SP at the dose of 5 mg/kg/day; HCD group fed 1% cholesterol; and HCD group with SP at the dose of 5 mg/kg/day. After 90 days of the experiment, blood samples were collected and the animals were killed; the thoracic aorta was stained by the Oil Red O staining method. The results indicate that plasma levels of cholesterol, triglycerides and malondialdehyde were increased in rabbits fed HCD. Plasma viscosity and whole blood viscosity were also higher in the HCD group than that in normal diet group. Treatment with SP prevented these alterations induced by HCD whereas this agent had no significant effect in rabbits fed normal diet. Morphological examination of the aorta revealed that SP treatment prevented the formation of foam cells and atherosclerotic plaque. It is suggested that the beneficial effects of SP in atherosclerosis may be due to actions on blood viscosity, lipid levels and oxidative stress.     

Upregulation of small GTPase RhoA in the basilar artery from diabetic (mellitus) rats

The goal of this study was to determine whether RhoA, a small GTPase, might be involved in the development of cerebral pathogenesis in diabetes. Male SD rats (n = 120) were divided into six groups: diabetic for 2, 4, 8 weeks, and an age-matched control group. Diabetes was induced by intravenous injection of streptozotocin (50 mg/kg). RhoA mRNA expression in basilar artery was measured by competitive RT-PCR. RhoA mRNA level was significantly increased in 4 weeks (184.1 +/- 28.5%, n = 7) and 8 weeks (218.7 +/- 24.5%, n = 7) after STZ injection compared to the age matched control basilar arteries (P < 0.05). Western blot was used to measure the membrane binding RhoA level to represent the activity of RhoA. We found that RhoA activity was strikingly increased in the diabetic basilar artery (n = 10 in each groups) compared to control basilar artery after STZ injection. Our data demonstrated that there was an upregulation of RhoA in the basilar artery of STZ induced diabetic rats, suggesting that RhoA might be involved in the cerebral vascular pathogenesis during diabetes mellitus.     

Marked heterogeneity of endothelin-mediated contractility and contraction dynamics in mouse renal and femoral arteries

Although endothelin (ET)-1 is one of the strongest known vasoconstrictors in most species, we and others have previously found that it is only weakly effective in the mouse aorta. The aim of this study was to further investigate vasoactive effects of ET-1 in vascular beds generally known to be particularly sensitive to ET-1, such as the renal artery. Experiments were performed to determine the vasoconstrictor responses in the thoracic aorta, and in the carotid, femoral, and renal arteries. Isolated vascular rings of C57BL/6 adult male mice (35-40 weeks of age) were exposed to ET-1 (0.01-300 nM) in the presence of the nitric oxide synthase inhibitor l-NAME (0.3 mM) to exclude effects of nitric oxide. Vessels from different vascular beds demonstrated distinct patterns in potency of the contractions to ET-1 and the dynamics of the responses. The maximal contraction to ET-1 was strong and significantly greater in the femoral (105 +/- 7% KCl) and renal artery (62 +/- 7% KCl) than in the carotid artery or the aorta (P < 0.05). The dynamics of the contractile response to ET-1 varied between the different vessels: the renal artery showed a rapid vasoconstriction, followed by a near complete loss of tension, whereas in the aorta, carotid, and femoral artery, vasoconstriction was more sustained. In conclusion, the data demonstrate that mouse femoral and renal arteries exhibit strong contractions in response to ET-1 compared with aorta and carotid artery, and that contractile dynamics differ markedly between arterial vascular beds. These findings may be important for studying the effects of endothelin in mouse models of human disease.     

Decreased pulmonary vascular responsiveness in rats raised on an essential fatty acid deficient diet

Leukotriene C4 is produced during hypoxic pulmonary vasoconstriction and leukotriene inhibitors preferentially inhibit the hypoxic pressor response in rats. If lipoxygenase products are important in hypoxic vasoconstriction, then an animal deficient in arachidonic acid should have a blunted hypoxic pressor response. We investigated if vascular responsiveness was decreased in vascular rings and isolated perfused lungs from rats raised on an essential fatty acid deficient diet (EFAD) compared to rats raised on a normal diet. Rats raised on the EFAD diet had decreased esterified plasma arachidonic acid and increased 5-, 8-, 11-eicosatrienoic acid compared to rats raised on the normal diet (control). Compared to the time matched responses in control isolated perfused lungs the pressor responses to angiotensin II and alveolar hypoxia were blunted in lungs from the arachidonate deficient rats. This decreased pulmonary vascular responsiveness was not affected by the addition of indomethacin or arachidonic acid to the lung perfusate. Similarly, the pulmonary artery rings from arachidonate deficient rats demonstrated decreased reactivity to norepinephrine compared to rings from control rats. In contrast, the tension increases to norepinephrine were greater in aortic rings from the arachidonate deficient rats compared to control. Stimulated lung tissue from the arachidonate deficient animals produced less slow reacting substance and platelet activating factor like material but the same amount of 6-keto-PGF1 alpha and TXB2 compared to control lungs. Thus there is an association between altered vascular responsiveness and impairment of stimulated production of slow reacting substance and platelet activating factor like material in rats raised on an EFAD diet.     

Decreased pulmonary vascular responsiveness in rats raised on an essential fatty acid deficient diet

Leukotriene C₄ is produced during hypoxic pulmonary vasoconstriction and leukotriene inhibitors preferentially inhibit the hypoxic pressor response in rats. If lipoxygenase products are important in hypoxic vasoconstriction, then an animal deficient in arachidonic acid should have a blunted hypoxic pressor response. We investigated if vascular responsiveness was decreased in vascular rings and isolated perfused lungs from rats raised on an essential fatty acid deficient diet (EFAD) compared to rats raised on a normal diet. Rats raised on the EFAD diet had decreased esterified plasma arachidonic acid and increased 5-, 8-, 11- eicosatrieonic acid compared to rats raised on the normal diet (control). Compared to the time matched responses in control isolated perfused lungs the pressor responses to angiotensin II and alveolar hypoxia were blunted in lungs from the arachidonate deficient rats. This decreased pulmonary vascular responsiveness was not affected by the addition of indomethacin or arachidonic acid to the lung perfusate. Similarly, the pulmonary artery rings from arichidonate deficient rats demonstrated decreased reactivity to norepinephrine compared to rings from control rats. In contrast, the tension increases to norepinephrine were greater in aortic rings from the arachidonate deficient rats compared to control. Stimulated lung tissue from the arachidonate deficient animals produced less slow reacting substance and platelet activating factor like material but the same amount of 6-keto-PGF_1α and TXB₂ compared to control lungs. Thus there is an associated between altered vascular responsiveness and impairment of stimulated production of slow reacting substance and platelet activating factor like materiali rat raised on an EFAD diet.     

Role of MAPK in chronic cerebral vasospasm

This study was undertaken to investigate the role of p44/42 MAPK in a dog double hemorrhage model of subarachnoid hemorrhage (SAH), and whether MEK inhibitors can alter the degree of SAH-induced vasoconstriction. The diameter of the basilar artery, which was compared with day 0 angiogram, decreased gradually in a time-dependent manner from day 3 (80%), day 5 (68%) through day 7 (53.5%). The level of MAPK (p44/42) immunoprecipitation peaked on day 3 and remained enhanced through day 7 (P < 0.05). MEK inhibitor PD98059 significantly reduced p44/42 MAPK immunoprecipitation and significantly reversed vasospasm and increased residual diameter to 79.0% on day 7. These results demonstrated that p44/42 MAPK kinase is involved in the pathogenesis of cerebral vasospasm. The MEK inhibitor PD98059 might be useful in the treatment of vasospasm.     

Amplification of sumatriptan-induced contraction in rabbit saphenous vein but not in basilar artery

The modulation of serotonin (5-HT(1B/1D)) receptor-induced vascular contractility by histamine and U-46619 was compared in the rabbit basilar artery and saphenous vein. In the saphenous vein, histamine (5 x 10(-7) M) significantly increased the potency (from pEC(50) of 6.0 to 6.8) and efficacy (from 52.3% to 88.2%) of sumatriptan. Likewise, U-46619 (5 x 10(-9) M) also increased the potency (from pEC(50) of 5.9 to 6.6) and efficacy (from 51.8% to 92.1%) of sumatriptan in the saphenous vein. In contrast, equieffective concentrations of histamine (10(-7) M) and U-46619 (3 x 10(-9) M) failed to amplify contraction to sumatriptan in the basilar artery. Contraction to sumatriptan was inhibited by nitrendipine (10(-7) M) in the basilar artery but not in the saphenous vein, suggesting that different contractile signaling mechanisms are operating in these tissues. Furthermore, U-46619- and thrombin-induced contractility in the basilar artery were also not amplified by histamine, suggesting that lack of amplification of contraction in the basilar artery was not restricted to sumatriptan but was rather a characteristic of this cerebral vessel. These data suggest that in the in vivo plasma milieu sumatriptan will more markedly contract the peripheral saphenous vein than the basilar artery, a cerebral blood vessel.     

颈性眩晕中医证型与经颅超声脑动脉血流检测结果的相关性分析

摘要 目的：分析颈性眩晕中医证型与经颅超声脑动脉血流检测结果的相关性。方法：选取2021年5月-2023年5月收治颈性眩晕患者作为研究对象,根据不同中医证型分为痰湿中阻组、肝阳上亢组、肝肾阴虚组和气血亏虚组,每组各纳入20例;并另选取健康体检患者30例作为对照组,均给予多普勒超声检查。分析不同中医证型者与对照组者多普勒超声检查特征与脑动脉血流变化[左右椎动脉、基底动脉及大脑中动脉收缩期峰值血流速度（VS）、平均血流速度(Vm)、舒张期峰值血流速度(Vd)及搏动指数(PI)]。结果：痰湿中阻组、肝肾阴虚组和气血亏虚组左右椎动脉、基底动脉及大脑中动脉VS均低于对照组（P＜0.05）;肝阳上亢组左右椎动脉、基底动脉及大脑中动脉VS均高于对照组（P＜0.05）;不同中医证型组间VS比较,肝阳上亢组＞痰湿中阻组＞肝肾阴虚组＞气血亏虚组;痰湿中阻组左右椎动脉、基底动脉均高于对照组（P＜0.05）,大脑中动脉Vm均低于对照组（P＜0.05）;肝阳上亢组左右椎动脉、基底动脉及大脑中动脉Vm均高于对照组（P＜0.05）;肝肾阴虚组左右椎动脉、基底动脉及大脑中动脉Vm均低于对照组（P＜0.05）;气血亏虚组大脑中动脉Vm均低于对照组（P＜0.05）,左右椎动脉、基底动脉Vm和对照组无显著性差异（P>0.05）;不同中医证型组间Vm比较,肝阳上亢组＞痰湿中阻组＞气血亏虚组＞肝肾阴虚组;痰湿中阻组左右椎动脉、基底动脉Vd均低于对照组（P＜0.05）,大脑中动脉Vd均高于对照组（P＜0.05）;肝阳上亢组左右椎动脉、基底动脉及大脑中动脉Vd均低于对照组（P＜0.05）;肝肾阴虚组左右椎动脉及大脑中动脉Vd均低于对照组（P＜0.05）,基底动脉Vd和对照组无差异（P＞0.05）;气血亏虚组左右椎动脉Vd均低于对照组（P＜0.05）,基底动脉Vd和对照组无差异（P＞0.05）,大脑中动脉Vd均高于对照组（P＜0.05）;不同中医证型组间Vd比较,气血亏虚组＞痰湿中阻组＞肝肾阴虚组＞肝阳上亢组;痰湿中阻组和气血亏虚组左右椎动脉、基底动脉及大脑中动脉PI均低于对照组（P＜0.05）;肝阳上亢组和肝肾阴虚组左右椎动脉、基底动脉及大脑中动脉PI均高于对照组（P＜0.05）;不同中医证型组间PI比较,肝阳上亢组＞肝肾阴虚组＞痰湿中阻组＞气血亏虚组。结论：不同中医证型的眩晕患者会出现不同程度脑动脉血流动力学异常,且不同组间存在差异,通过经颅多普勒超声检查,可以对眩晕中医证型提供参考价值。     

Development of atherosclerotic lesions in cholesterol-loaded rabbits.

To examine both of the target vessels and the optimal time of their endothelial denudation to study vascular restenosis after balloon injury in cholesterol-loaded rabbits, we made 36 atherosclerotic rabbits by feeding a hypercholesterol diet, and histologically examined the onset time and the development of atherosclerosis. Atheromatous changes were observed first after the 5th week in the thoracic aorta from the start of the diet, and then extended to the abdominal aorta, coronary artery with time. The atherosclerotic lesions in the thoracic aorta and the proximal portion of the coronary artery showed high-grade concentric intimal thickening with luminal stenosis. The abdominal aortic lesion mildly progressed. In the renal, carotid and femoral arteries, in contrast, slight atheroscleromatous changes developed during the diet period. These results suggest that the thoracic and abdominal aortas and the coronary artery would be suitable as target vessels to study vascular restenosis after balloon injury, and the endothelial denudation of these vessels should be performed between the 8th and 15th week in this diet protocol for an accurate analysis.     

Metabolism of sphingolipids by normal and atherosclerotic aorta of squirrel monkeys

We studied the synthesis and hydrolysis of sphingomyelin by homogenates of aortic intima plus inner media from normal squirrel monkeys and from monkeys with nutritionally-induced atherosclerosis (6-10 mo on a semi-purified diet containing butter and cholesterol). The concentrations of sphingomyelin in the aortas and plasmas of the atherosclerotic monkeys were higher than those for the normal monkeys. Palmitoyl-1-(14)C coenzyme A was actively utilized for the synthesis of ceramide (N-palmitoyl sphingosine). The addition of sphingosylphosphorylcholine increased the utilization of palmitoyl CoA in sphingomyelin synthesis, and the addition of psychosine (sphingosyl galactoside) increased the incorporation of palmitate into cerebrosides. Rates of sphingomyelin and ceramide synthesis were significantly higher in the atherosclerotic than in the control aortas. Hydrolysis of labeled sphingomyelin to ceramide was also increased in homogenates of the atherosclerotic aortas. Labeled sphingomyelin was taken up from plasma by everted carotid arteries, and this process was also enhanced by atherosclerosis. Increased rates of synthesis and of uptake from plasma of sphingomyelin may account for the increased concentrations of sphingomyelin in the atherosclerotic arteries, even though the ability to degrade sphingomyelin is also enhanced in the atherosclerotic aorta.     

Evaluation of the anti-atherogenic potential of chrysin in Wistar rats

Hypercholesterolemia is one of the major risk factors that precipitate coronary heart disease and atherosclerosis. Oxidative stress is believed to contribute to the pathogenesis of hypercholesterolemic atherosclerosis; hence, various antioxidant compounds are being evaluated for potential anti-atherogenic effects. In the present study, the putative anti-atherogenic and antioxidant efficacy of a flavonoid, chrysin, was evaluated in an experimental model of atherosclerosis. In male, albino Wistar rats fed an atherogenic diet for 45 days and treated with saline, significantly higher mean levels of serum lipid profile parameters (total cholesterol, triglycerides, low-density, and very low-density lipoprotein cholesterol), lower mean levels of high-density lipoprotein cholesterol and higher mean serum levels of hepatic marker enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase) were observed when compared with the levels in rats fed a control diet. In addition, significantly lower mean hepatic levels of lipoprotein lipase, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and non-enzymatic antioxidants (reduced glutathione, and vitamins C and E), and a significantly higher mean level of hepatic malondialdehyde (MDA) were noted in comparison to the values in control rats. In atherogenic diet-fed rats that received chrysin orally (200 mg/kg b.wt) for 15 days, starting 30 days after the start of the atherogenic diet, significantly lower mean serum levels of lipid profile parameters (except for HDL-cholesterol which was elevated), hepatic marker enzymes, and significantly higher mean hepatic levels of LPL, HMG-CoA reductase, enzymatic, and non-enzymatic antioxidants and significantly lower mean levels of hepatic MDA were noted, compared to the values in atherogenic diet-fed, saline-treated rats. Histopathological studies appeared to suggest the protective effect of chrysin on the hepatic tissue and aorta of atherosclerotic rats. These results suggest that chrysin has anti-atherogenic potential in an experimental setting.     

冠状动脉粥样硬化大鼠实验动物模型的改进与评价

目的通过对文献报道的动脉粥样硬化大鼠造模方法的改进,建立一种适合进行心血管疾病研究的冠状动脉粥样硬化Wistar大鼠模型。方法将40只大鼠随机分为对照组与模型组,对照组15只,模型组25只。模型组高脂饲料喂养配合前3个月,每月按15万U/kg每月腹腔注射维生素D3一次,对照组喂养普通饲料,造模时长150 d。实验结束后通过对血管内皮、脂代谢、炎症浸润几个方面对模型大鼠进行考察。结果证实模型组大鼠较对照组血清LDL-C、CHO、TG水平明显升高,HDL-C/LDL-C、NO/ET-1值明显降低;AI值显著增高;血清NO、ET-1、ox-LDL、AngⅡ、sICAM-1表达明显增高;HE染色显示：模型组大鼠冠状动脉出现血栓、内皮破坏、粥样斑块形成,血管壁钙化情况;心肌纤维组织增生,炎细胞浸润,心肌轻度变性;主动脉出现动脉粥样硬化斑块形成,而对照组无病变产生。结论本方法能够提供一种稳定的、复制性好的用于冠状动脉粥样硬化实验研究的大鼠模型。     

G?ttingen miniature swine as a model for diet-induced atherosclerosis

Twenty-four G?ttingen Miniature Swine/csk, in order to evaluate their potential usefulness as a model for experimental atherosclerosis studies, were fed diets of three types, a high-fat plus high cholesterol diet, a high-fat diet, and a commercial diet. Each group consisted of 4 males and 4 females. Swine fed the experimental diet were investigated by gross, microscopic and serum biochemical examination on the 1st, 3rd, 6th and 9th month after start of experimentation. Lesions of atherosclerosis were observed in the high-fat plus high-cholesterol diet group. After a month on the experimental diet, intimal thickening was detected in the abdominal aorta just above the origin of internal iliac artery, left coronary artery and ascending aorta by microscopic examination. Thereafter, on the 9th month after the start, there was more extensive and severe atherosclerosis. These lesions were classified into two types by the difference in the histologic architecture of arterial wall. One was fatty streaks that were in thoracic aorta belonging to the elastic type and the other was fibrous plaques that were in abdominal aorta and iliac artery and so on, belong to the transitional or muscular type. High-fat plus high-cholesterol diet feeding led to elevated serum cholesterol and beta-lipoprotein levels, and had an effect on several kinds of metabolism. All of the swine fed high-fat or commercial diet had little gross, microscopic lesions and had no change in serum cholesterol and beta-lipoprotein levels. Hypercholesterolemia and hyper-beta-lipoproteinemia had a close relation to the development and acceleration of atherosclerosis. It was possible to show that the diet induced atherosclerosis was similar in quality to that observed in humans, and that the G?ttingen miniature swine was a suitable animal for the study of atherosclerosis.     

慢性阻断血管紧张素Ⅱ1型受体不能完全防止模拟失重大鼠血管的适应性结构变化

我们以前的工作提示,在模拟失重所引起的血管区域特异性适应变化中,局部肾素．血管紧张素系统（local reninangiotensin system,L-RAS）可能发挥关键调控作用。本文以losartan慢性阻断血管紧张素Ⅱ1型受体（angiotensin Ⅱtypelreceptor,AT1R）,观察模拟失重是否仍能引起血管的这种适应性改变,并检测大血管管壁L-RAS主要成分的表达是否也发生相应变化。以尾部悬吊大鼠模型模拟失重的生理影响。制作基底动脉、胫前动脉、颈总动脉和腹主动脉的HE染色切片,在光学显微镜下进行形态观测：用免疫组织化学技米测量颈总动脉和腹主动脉壁的血管紧张素原（angiotensinogen,AGT）及AT-R的表达变化。结果表明：4周模拟失重引起大鼠基底动脉中膜和颈总动脉管壁各平滑肌肌层肥厚,而胫前动脉和腹主动脉则发生萎缩性改变;给予losartan4周引起上述4种血管皆发生萎缩性变化;阻断AT1R,模拟失重仍然能引起基底动脉、颈总动脉发生相对肥厚性改变和腹主动脉萎缩加重。4周模拟失重还引起颈总动脉壁中AGT和AT1R表达上调,而腹主动脉壁及血管周围组织中AGT和AT1R表达下调;给予losartan4周仅引起腹主动脉壁中AGT和AT1R表达减少;阻断AT1R,模拟失重使腹主动脉壁AT1R表达进一步减少。结果提示,4周模拟失重引起大鼠脑、颈部与后身大、中动脉血管的形态结构改变和L-RAS主要成分表达发生上调或下调,血管L-RAS在其中可能发挥关键性调控作用;但在慢性阻断AT1R的条件下,其它调控机制仍可能在脑血管适应性调节中发挥一定作用。     

G-CSF prevents the progression of atherosclerosis and neointimal formation in rabbits

Granulocyte colony-stimulating factor (G-CSF) prevents left ventricular remodeling after myocardial infarction, but its effect on atherosclerosis is unknown. We examined two kinds of rabbit atherosclerosis models. Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHL-MI) rabbits were treated with G-CSF or saline for 7 days from 14 months old. The vascular injury models were created by inflating angioplasty balloon in the iliac artery of rabbits and were divided into G-CSF and saline group. G-CSF significantly reduced the stenosis score of coronary artery and lipid plaque area of thoracic aorta in WHHL-MI rabbits at 4 weeks after the treatment. In the vascular injury model, G-CSF significantly prevented an increase in neointima/media ratio at 4 weeks after the treatment. G-CSF accelerated the reendothelialization of denuded arteries, and the pretreatment with nitric oxide synthase inhibitor significantly inhibited it. These results suggest that G-CSF has a therapeutic potential for the progression of atherosclerosis.     

Effects of miltefosine treatment in fibroblast cell cultures and in mice experimentally infected with Neospora caninum tachyzoites

Miltefosine was investigated for its activity against Neospora caninum tachyzoites in vitro, and was shown to inhibit the proliferation of N. caninum tachyzoites cultured in human foreskin fibroblasts (HFF) with an IC50 of 5·2 μM. Treatment of infected cells with 25 μM miltefosine for a period of 10 h had only a parasitostatic effect, while after 20 h of treatment parasiticidal effects were observed. This was confirmed by transmission electron microscopy of N. caninum-infected and miltefosine-treated HFF. Administration of miltefosine to N. caninum-infected Balb/c female mice at 40 mg/kg/day for 14 days resulted in 6 out of 10 mice exhibiting weight loss, ruffled coat and apathy between days 7 and 13 post-infection. In the group that received placebo, only 2 out of 8 mice succumbed to infection, but the cerebral burden was significantly higher compared to the miltefosine treatment group. In a second experiment, the time-span of treatment was reduced to 5 days, and mice were maintained without further treatment for 4 weeks. Only 2 out of 9 mice in the miltefosine treatment group exhibited signs of disease, while 8 out of 10 mice succumbed to infection in the placebo group. These results showed that miltefosine hampered the dissemination of parasites into the CNS during experimental N. caninum infection in mice.     

The ultrastructural basis of the permeability of arterial endothelium to horseradish peroxidase

The thoracic aorta and basilar artery, in which the incidence of atherosclerosis is known to be different, were examined to elucidate the correlation between the structure of the intercellular cleft junction between adjacent endothelial cells and its permeability to HRP. Tannic acid or HRP in the vessel lumen passed through the intercellular clefts of the thoracic aorta into the subendothelial space, whereas in the basilar artery they were unable to penetrate beyond the tight junction of the intercellular clefts. Freeze-fracture replicas revealed that the tight junctions of the thoracic aorta consisted of one to two junctional strands in most areas of the cleaved planes, with discontinuities in some places, whereas those of the basilar artery consisted of a continuous belt-like meshwork of six anastomosing junctional strands on average. These observations confirm that the structure of endothelial junctions in arteries has a close correlation with the permeability of the intercellular clefts to HRP.