血管生成素及其受体在颅内动脉瘤的表达和临床意义的研究
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摘要
研究目的
颅内动脉瘤(intracranial aneurysms, ICA)是引起自发性蛛网膜下腔出血(subarachnoid hemorrhage, SAH)的主要原因之一。观察ICA瘤壁结构变化和血管生成素-1&-2(Angiopoietin-1&-2)及其受体Tie-2在ICA病理结构和患者血清中的表达,探讨ICA形成和破裂出血的机制,为临床治疗提供相应依据。
研究方法
选取2009年12月～2010年7月天津医科大学总医院神经外科和天津市脑系科中心医院(环湖医院)神经外科十四病区收治颅内动脉瘤患者41例作为研究对象。研究对象中男16例,女25例,年龄平均为(50.63±10.11)岁,体质量指数BMI为(23.11±2.30)kg/m2。所有病例均经影像学检查(CTA或DSA)证实为单发颅内动脉瘤,均为首诊病例,入院前均未经正规治疗,入院后均行开颅动脉瘤夹闭手术。
第一部分
采集41例ICA患者入院后正规治疗前血清样品41份作为研究组。选取同期于天津医科大学总医院健康管理中心体检的正常查体者血清样品40例作为对照组。记录2组的基本情况,包括性别、年龄、体质量指数BMI、空腹血糖水平、吸烟和嗜酒史。采用酶联免疫吸附法(ELISA法)检测所有血清样品的Ang-1、Ang-2及其受体Tie-2的表达水平。采用单盲方式,使用统计学方法对2组血清样品Ang-1、Ang-2及其受体Tie-2检测结果进行数据分析。同时根据颅内动脉瘤Hunt-Hess临床分级将动脉瘤性蛛网膜下腔出血(aSAH)患者36例分为轻症亚组(Ⅰ～Ⅲ级)和重症亚组(Ⅳ～Ⅴ级)；根据是否服用他汀类降脂药将41例ICA患者分为两组,采用以上统计方法进行数据分析。
第二部分
选取第一部分病例中进行开颅手术并完成3周以上住院治疗的病人20例作为研究对象,均为破裂动脉瘤,研究组内男7例,女13例,年龄(50.75±11.70)岁。选取同期行开颅手术的高血压脑出血患者15例作为对照组。采集入院时、入院后1w和3w三个时间点血清标本,采用酶联免疫吸附法(ELISA法)检测所有血清样品的Ang-1、Ang-2及其受体Tie-2的表达水平。采用单盲方式,使用统计学方法对2组血清样品Ang-1、Ang-2及其受体Tie-2检测结果进行数据分析。
第三部分
以第一部分所述ICA行开颅动脉瘤夹闭术患者术中获取的动脉瘤标本21例作为研究对象。研究组中男9例,女12例,年龄(53.38±11.47)岁,其中左后交通动脉瘤6例,右后交通动脉瘤7例,前交通动脉瘤3例,左大脑中动脉动脉瘤2例,右大脑中动脉动脉瘤3例。以手术中获取的手术入路同侧颞浅动脉12例(男性6例,女性6例)作为正常对照组,其中左侧4例,右侧8例。通过HE染色观察ICA瘤壁整体结构变化,通过免疫组化染色观察α-SMA和Ang-1、Ang-2及其受体Tie-2在ICA瘤壁的表达水平,采用专用软件进行图像采集,选取参数积分光密度值(IOD)进行测量。采用单盲方式,使用统计学方法对记录的2组α-SMA和Ang-1、Ang-2及其受体Tie-2的IOD进行数据分析。
结果
1、结果显示,ICA患者(41例)与正常查体者(40例)入院时SBP和DBP比较差异有统计学意义(P<0.05),ICA组高于对照组；血清Ang-1、Ang-2和受体Tie-2比较差异有统计学意义(P<0.05),ICA组的血清Ang-1、Ang-2和Tie-2均高于对照组。
2、根据颅内动脉瘤Hunt-Hess临床分级可将aSAH患者(36例)分为轻症亚组(即Ⅰ～Ⅲ级)和重症亚组(即Ⅳ～Ⅴ级)。两亚组患者的动脉瘤直径、入院时SBP比较差异均没有统计学意义(P>0.05)；两亚组入院时DBP、血清Ang-1水平和Ang-2水平比较差异有统计学意义(P<0.05),重症亚组高于轻症亚组；两亚组Tie-2水平比较差异没有统计学意义(P>0.05),重症亚组略低于轻症亚组。
3、服用他汀类降脂药组与非服药组比较,血清Ang-1、Ang-2和受体Tie-2的表达水平差异有统计学意义(P<0.05),服药组三项指标均低于非服药组。
4、aSAH患者组(20例)与同期高血压脑出血患者组(15例)血清Ang-1、Ang-2在时间上的变化趋势比较,差别有统计学意义(F时间Ang-1=83.457, F时间Ang-2=8.029, P<0.05)。血清Tie-2在时间上的变化趋势比较,差别没有统计学意义(F时间Tie-2=0.596,P>0.05)。
5、在光镜下观察,动脉瘤壁全部或局部变薄、扩张,多数呈现有几层变性的平滑肌或纤维化的组织维持着动脉瘤壁的结构,同时可见内皮细胞退行性变,常可见内皮细胞排列中断,部分瘤壁内有钙化和透明变性,瘤腔内充满血凝块,有的血凝块已经纤维化。免疫组化染色α-SMA表达结果显示,与对照组(颞浅动脉)比较,颅内动脉瘤瘤壁α-SMA表达呈弱阳性,可以看到动脉瘤壁血管平滑肌数量明显减少,排列紊乱,形态异常,两组光密度值(IOD)比较差异有统计学意义(P<0.05)。
6、光镜下观察,Ang-1在颅内动脉瘤瘤壁组织内主要表达于血管平滑肌细胞和部分成纤维细胞,以中外膜表达为主,部分存在内膜增厚表现的病例,因血管平滑肌迁徙进入内膜,内膜也可见Ang-1表达。Ang-2和Tie-2在颅内动脉瘤瘤壁组织内主要表达于血管内皮细胞,少量表达于平滑肌细胞及成纤维细胞。在研究组(颅内动脉瘤)中Ang-1呈弱阳性表达,在对照组(颞浅动脉)Ang-1呈强阳性表达；在研究组(颅内动脉瘤)中Ang-2呈强阳性表达,在对照组(颞浅动脉)Ang-2呈弱阳性表达。两组中反应Ang-1、Ang-2表达的IOD值比较,差异有统计学意义(均P<0.05)。受体Tie-2在两组均呈阳性表达,IOD值比较,差异没有统计学意义(P>0.05)。
结论
1、ICA瘤壁组织中血管平滑肌细胞凋亡异常增多,与增殖比例失衡,导致了平滑肌细胞数量的减少,内皮破坏,中膜损伤,容易破裂出血。Ang-1、Ang-2及其受体Tie-2的表达位点和表达水平与动脉瘤壁损伤、平滑肌凋亡的学说吻合,可能成为今后揭开ICA形成和破裂原因的主要研究方向之一
2、Angiopoietins不仅在胚胎发育过程中存在,而且在创伤修复、肿瘤、炎症等血管生成过程中发挥重要作用。Ang/Tie-2作为血管生成调节因子与颅内动脉瘤的形成和破裂机制有关,这为动脉瘤的治疗开辟了一条新的道路,随着其基因及相关蛋白的研究深入,有可能通过基因调控和特异性抗体阻断Ang与受体结合,为临床上非手术治疗动脉瘤或减少开颅夹闭动脉瘤手术的风险提供新的思路。
3、血清学检查在临床简单易行,血清Ang表达水平的变化已经成为国内外一些诸如膀胱癌、结肠癌和脑胶质瘤等恶性肿瘤学研究领域正在探讨的有可能的临床预后判别指标,但是在脑血管病领域,特别是ICA的研究方面此类报道尚未得见。通过分析血清Ang-1、Ang-2及其受体Tie-2表达的临床意义,为探讨可能的ICA破裂的病理生理机制提供新的参考,同时血清学检测也有可能成为判定aSAH预后的重要指标,具有重要的临床意义和实用价值。
Background
Aneurysmal subarachnoid hemorrhage (aSAH) are vascular lesions that often present as cerebral hemorrhage in adults. Human intracranial aneurysms (ICA) are associated with endothelial activation. Angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) are major regulators of endothelial activation and integrity. The aim of this study was to investigate the clinical utility of angiopoietins levels as biomarkers of disease in human intracranial aneurysms.
Objective
To investigate the effect of the levels of Ang-1, Ang-2 and Tie-2 in ICA.
Methods
We carried out a free ICA screening in Tianjin.41 patients with ruptured (n=36) and unruptured (n=5) ICA and 40 healthy control subjects were recruited from December 2009 to June 2010. All the patients were diagnosed by CTA or DSA. And the operations were carried out
Part A
Serum samples were collected as follows:40 from control subjects,41 from patients with ICA. Serum levels of Ang-1, Ang-2 and receptor Tie-2 were tested by enzymelinked immunosorbent assay (ELISA), and compared between patients with ICA and control subjects by statistical methods. The levels of serum Ang-1,Ang-2 and Tie-2 in the patients of Hunt-HessⅠ～Ⅴwere measured.
Part B
Serum samples were collected as follows:15 from patients with hypertensive cerebra 1 hemorrhage (ICH),20 from patients with aSAH. Serum levels of Angl, Ang2 and Tie-2 of all patients in Od,7d and 21d were tested by enzymelinked immunosorbent assay (ELISA) and compared patients with aSAH and patients with ICH by statistical methods.
Part C
Pathological samples were collected as follows:12 of normal blood vessels,21 of ICA.The expression of Angl, Ang2, Tie-2 and structural changes in ICAs were observed with immunohistochemistry and microscopic technique respectively. The levels of Ang-1, Ang-2 and receptor Tie-2 were tested, and compared between patients with ICA and normal blood vessels by statistical methods.
Results
1. The levels of serum Ang-1 (t=8.344, P=0.000), Ang-2 (t=2.289, P=0.025), Tie-2 (t=2.481, P=0.015), SBP (t=10.154,P=0.000) and DBP (t=5.905,P=0.000) of ICA patients had significant higher levels, when compared with control subjects.
2. The levels of serum Ang-1 (t=-6.497, P=0.000), Ang-2 (t=-4.405,P=0.000) and DBP (t=-2.162, P=0.038) in the patients of aSAH Hunt-HessⅠ～Ⅲwere significantly lower than them of aSAH Hunt-Hess IV-V.
3. The tendency levels of serum Ang-1 (Ftime=83.457) and Ang-2 (F time=8.029) in the patients of aSAH were significantly higher than them of ICH in Od,7d and 21d (P<0.05).
4. Endothelial cells of ICAs were degenerated and collaped and a number of vesicles and swollen mitochondria were present in the cytoplasm. The ICA wall varied in thickness and was composed of regenerative smooth muscle cells and collagenous fibres.
5. Ang-1 (t=-28.034, P=0.000), Ang-2 (t=6.238, P=0.000) and a-SMA (t=-13.067, P=0.000) was overexpressed in ICAs, when compared with that of normal blood vessels.
Conclusions
1. The expression of Ang-1, Ang-2 and receptor Tie-2 and vascular degenerative changes might play an important role in the pathogenesis and rupture of ICAs.
2. A novel hypothesis in the formation and progression of ICAs has been proposed.
3.These results suggest that serum Ang-1 and Ang-2 levels are promising clinically informative biomarkers of disease severity in aSAH.
颅内动脉瘤(intracranial aneurysms, ICA)是引起自发性蛛网膜下腔出血(subarachnoid hemorrhage, SAH)的主要原因之一。观察ICA瘤壁结构变化和血管生成素-1&-2(Angiopoietin-1&-2)及其受体Tie-2在ICA病理结构和患者血清中的表达,探讨ICA形成和破裂出血的机制,为临床治疗提供相应依据。
研究方法
选取2009年12月～2010年7月天津医科大学总医院神经外科和天津市脑系科中心医院(环湖医院)神经外科十四病区收治颅内动脉瘤患者41例作为研究对象。研究对象中男16例,女25例,年龄平均为(50.63±10.11)岁,体质量指数BMI为(23.11±2.30)kg/m2。所有病例均经影像学检查(CTA或DSA)证实为单发颅内动脉瘤,均为首诊病例,入院前均未经正规治疗,入院后均行开颅动脉瘤夹闭手术。
第一部分
采集41例ICA患者入院后正规治疗前血清样品41份作为研究组。选取同期于天津医科大学总医院健康管理中心体检的正常查体者血清样品40例作为对照组。记录2组的基本情况,包括性别、年龄、体质量指数BMI、空腹血糖水平、吸烟和嗜酒史。采用酶联免疫吸附法(ELISA法)检测所有血清样品的Ang-1、Ang-2及其受体Tie-2的表达水平。采用单盲方式,使用统计学方法对2组血清样品Ang-1、Ang-2及其受体Tie-2检测结果进行数据分析。同时根据颅内动脉瘤Hunt-Hess临床分级将动脉瘤性蛛网膜下腔出血(aSAH)患者36例分为轻症亚组(Ⅰ～Ⅲ级)和重症亚组(Ⅳ～Ⅴ级)；根据是否服用他汀类降脂药将41例ICA患者分为两组,采用以上统计方法进行数据分析。
第二部分
选取第一部分病例中进行开颅手术并完成3周以上住院治疗的病人20例作为研究对象,均为破裂动脉瘤,研究组内男7例,女13例,年龄(50.75±11.70)岁。选取同期行开颅手术的高血压脑出血患者15例作为对照组。采集入院时、入院后1w和3w三个时间点血清标本,采用酶联免疫吸附法(ELISA法)检测所有血清样品的Ang-1、Ang-2及其受体Tie-2的表达水平。采用单盲方式,使用统计学方法对2组血清样品Ang-1、Ang-2及其受体Tie-2检测结果进行数据分析。
第三部分
以第一部分所述ICA行开颅动脉瘤夹闭术患者术中获取的动脉瘤标本21例作为研究对象。研究组中男9例,女12例,年龄(53.38±11.47)岁,其中左后交通动脉瘤6例,右后交通动脉瘤7例,前交通动脉瘤3例,左大脑中动脉动脉瘤2例,右大脑中动脉动脉瘤3例。以手术中获取的手术入路同侧颞浅动脉12例(男性6例,女性6例)作为正常对照组,其中左侧4例,右侧8例。通过HE染色观察ICA瘤壁整体结构变化,通过免疫组化染色观察α-SMA和Ang-1、Ang-2及其受体Tie-2在ICA瘤壁的表达水平,采用专用软件进行图像采集,选取参数积分光密度值(IOD)进行测量。采用单盲方式,使用统计学方法对记录的2组α-SMA和Ang-1、Ang-2及其受体Tie-2的IOD进行数据分析。
结果
1、结果显示,ICA患者(41例)与正常查体者(40例)入院时SBP和DBP比较差异有统计学意义(P<0.05),ICA组高于对照组；血清Ang-1、Ang-2和受体Tie-2比较差异有统计学意义(P<0.05),ICA组的血清Ang-1、Ang-2和Tie-2均高于对照组。
2、根据颅内动脉瘤Hunt-Hess临床分级可将aSAH患者(36例)分为轻症亚组(即Ⅰ～Ⅲ级)和重症亚组(即Ⅳ～Ⅴ级)。两亚组患者的动脉瘤直径、入院时SBP比较差异均没有统计学意义(P>0.05)；两亚组入院时DBP、血清Ang-1水平和Ang-2水平比较差异有统计学意义(P<0.05),重症亚组高于轻症亚组；两亚组Tie-2水平比较差异没有统计学意义(P>0.05),重症亚组略低于轻症亚组。
3、服用他汀类降脂药组与非服药组比较,血清Ang-1、Ang-2和受体Tie-2的表达水平差异有统计学意义(P<0.05),服药组三项指标均低于非服药组。
4、aSAH患者组(20例)与同期高血压脑出血患者组(15例)血清Ang-1、Ang-2在时间上的变化趋势比较,差别有统计学意义(F时间Ang-1=83.457, F时间Ang-2=8.029, P<0.05)。血清Tie-2在时间上的变化趋势比较,差别没有统计学意义(F时间Tie-2=0.596,P>0.05)。
5、在光镜下观察,动脉瘤壁全部或局部变薄、扩张,多数呈现有几层变性的平滑肌或纤维化的组织维持着动脉瘤壁的结构,同时可见内皮细胞退行性变,常可见内皮细胞排列中断,部分瘤壁内有钙化和透明变性,瘤腔内充满血凝块,有的血凝块已经纤维化。免疫组化染色α-SMA表达结果显示,与对照组(颞浅动脉)比较,颅内动脉瘤瘤壁α-SMA表达呈弱阳性,可以看到动脉瘤壁血管平滑肌数量明显减少,排列紊乱,形态异常,两组光密度值(IOD)比较差异有统计学意义(P<0.05)。
6、光镜下观察,Ang-1在颅内动脉瘤瘤壁组织内主要表达于血管平滑肌细胞和部分成纤维细胞,以中外膜表达为主,部分存在内膜增厚表现的病例,因血管平滑肌迁徙进入内膜,内膜也可见Ang-1表达。Ang-2和Tie-2在颅内动脉瘤瘤壁组织内主要表达于血管内皮细胞,少量表达于平滑肌细胞及成纤维细胞。在研究组(颅内动脉瘤)中Ang-1呈弱阳性表达,在对照组(颞浅动脉)Ang-1呈强阳性表达；在研究组(颅内动脉瘤)中Ang-2呈强阳性表达,在对照组(颞浅动脉)Ang-2呈弱阳性表达。两组中反应Ang-1、Ang-2表达的IOD值比较,差异有统计学意义(均P<0.05)。受体Tie-2在两组均呈阳性表达,IOD值比较,差异没有统计学意义(P>0.05)。
结论
1、ICA瘤壁组织中血管平滑肌细胞凋亡异常增多,与增殖比例失衡,导致了平滑肌细胞数量的减少,内皮破坏,中膜损伤,容易破裂出血。Ang-1、Ang-2及其受体Tie-2的表达位点和表达水平与动脉瘤壁损伤、平滑肌凋亡的学说吻合,可能成为今后揭开ICA形成和破裂原因的主要研究方向之一
2、Angiopoietins不仅在胚胎发育过程中存在,而且在创伤修复、肿瘤、炎症等血管生成过程中发挥重要作用。Ang/Tie-2作为血管生成调节因子与颅内动脉瘤的形成和破裂机制有关,这为动脉瘤的治疗开辟了一条新的道路,随着其基因及相关蛋白的研究深入,有可能通过基因调控和特异性抗体阻断Ang与受体结合,为临床上非手术治疗动脉瘤或减少开颅夹闭动脉瘤手术的风险提供新的思路。
3、血清学检查在临床简单易行,血清Ang表达水平的变化已经成为国内外一些诸如膀胱癌、结肠癌和脑胶质瘤等恶性肿瘤学研究领域正在探讨的有可能的临床预后判别指标,但是在脑血管病领域,特别是ICA的研究方面此类报道尚未得见。通过分析血清Ang-1、Ang-2及其受体Tie-2表达的临床意义,为探讨可能的ICA破裂的病理生理机制提供新的参考,同时血清学检测也有可能成为判定aSAH预后的重要指标,具有重要的临床意义和实用价值。
Background
Aneurysmal subarachnoid hemorrhage (aSAH) are vascular lesions that often present as cerebral hemorrhage in adults. Human intracranial aneurysms (ICA) are associated with endothelial activation. Angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) are major regulators of endothelial activation and integrity. The aim of this study was to investigate the clinical utility of angiopoietins levels as biomarkers of disease in human intracranial aneurysms.
Objective
To investigate the effect of the levels of Ang-1, Ang-2 and Tie-2 in ICA.
Methods
We carried out a free ICA screening in Tianjin.41 patients with ruptured (n=36) and unruptured (n=5) ICA and 40 healthy control subjects were recruited from December 2009 to June 2010. All the patients were diagnosed by CTA or DSA. And the operations were carried out
Part A
Serum samples were collected as follows:40 from control subjects,41 from patients with ICA. Serum levels of Ang-1, Ang-2 and receptor Tie-2 were tested by enzymelinked immunosorbent assay (ELISA), and compared between patients with ICA and control subjects by statistical methods. The levels of serum Ang-1,Ang-2 and Tie-2 in the patients of Hunt-HessⅠ～Ⅴwere measured.
Part B
Serum samples were collected as follows:15 from patients with hypertensive cerebra 1 hemorrhage (ICH),20 from patients with aSAH. Serum levels of Angl, Ang2 and Tie-2 of all patients in Od,7d and 21d were tested by enzymelinked immunosorbent assay (ELISA) and compared patients with aSAH and patients with ICH by statistical methods.
Part C
Pathological samples were collected as follows:12 of normal blood vessels,21 of ICA.The expression of Angl, Ang2, Tie-2 and structural changes in ICAs were observed with immunohistochemistry and microscopic technique respectively. The levels of Ang-1, Ang-2 and receptor Tie-2 were tested, and compared between patients with ICA and normal blood vessels by statistical methods.
Results
1. The levels of serum Ang-1 (t=8.344, P=0.000), Ang-2 (t=2.289, P=0.025), Tie-2 (t=2.481, P=0.015), SBP (t=10.154,P=0.000) and DBP (t=5.905,P=0.000) of ICA patients had significant higher levels, when compared with control subjects.
2. The levels of serum Ang-1 (t=-6.497, P=0.000), Ang-2 (t=-4.405,P=0.000) and DBP (t=-2.162, P=0.038) in the patients of aSAH Hunt-HessⅠ～Ⅲwere significantly lower than them of aSAH Hunt-Hess IV-V.
3. The tendency levels of serum Ang-1 (Ftime=83.457) and Ang-2 (F time=8.029) in the patients of aSAH were significantly higher than them of ICH in Od,7d and 21d (P<0.05).
4. Endothelial cells of ICAs were degenerated and collaped and a number of vesicles and swollen mitochondria were present in the cytoplasm. The ICA wall varied in thickness and was composed of regenerative smooth muscle cells and collagenous fibres.
5. Ang-1 (t=-28.034, P=0.000), Ang-2 (t=6.238, P=0.000) and a-SMA (t=-13.067, P=0.000) was overexpressed in ICAs, when compared with that of normal blood vessels.
Conclusions
1. The expression of Ang-1, Ang-2 and receptor Tie-2 and vascular degenerative changes might play an important role in the pathogenesis and rupture of ICAs.
2. A novel hypothesis in the formation and progression of ICAs has been proposed.
3.These results suggest that serum Ang-1 and Ang-2 levels are promising clinically informative biomarkers of disease severity in aSAH.
引文
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