体表海锦状静脉畸形病理机制初步研究
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摘要
目的 从病理结构着手研究体表海绵状静脉畸形的发病机制。(1)观察海绵状静脉畸形病理结构，研究畸形血窦中内皮细胞和平滑肌细胞的表型与分布；(2)研究畸形血窦中结构蛋白和血管形成因子表达，探讨海绵状静脉畸形血窦壁结构异常的机理；(3)研究海绵状静脉畸形组织及其周围组织中神经纤维分布，探讨神经纤维分布与海绵状静脉畸形的关系。
方法 挑选我院未经治疗单纯手术切除并经病理确诊的海绵状静脉畸形标本共42例；从其他手术中获取正常中型静脉和小静脉标本各12例。(1) 所有标本均行·HE染色，观察海绵状静脉畸形的病理结构，重点观察畸形血窦壁和正常小静脉壁中的内皮细胞和平滑肌细胞分布并计数。(2)选取25例海绵状静脉畸形标本以及正常中小静脉标本各12例，行EnVision法免疫组化染色。①用抗特异性内皮细胞抗原CD31和血管平滑肌细胞标志α-平滑肌肌动蛋白的单克隆抗体染色观察血窦壁内皮细胞和平滑肌细胞的表型。②应用抗Ⅳ型胶原、纤维连接蛋白和层粘连蛋白的单克隆抗体染色观察血管壁中结构蛋白表达。③应用抗血管内皮生长因子、转化生长因子-β_1以及血管生成素-1的单克隆抗体染色观察血管壁中血管形成因子表达。④应用抗神经元特异性烯醇化酶和神经微丝蛋白的单克隆抗体染色比较海绵状静脉畸形组织和正常中小静脉周围组织中神经纤维的分布。
结果 (1)海绵状静脉畸形血窦的血窦半径与血窦壁厚度的比例远大于正常中小静脉，畸形血窦腔扩大而血窦壁没有相应增厚。(2)畸形血窦壁中平滑肌细胞和内皮细胞的比例显著低于正常小静脉，α-SMA在畸形血窦的表达明显低于中小静脉，其排列紊乱，CD31表达相似。(3)Ⅳ型胶原、纤维连接蛋白和层粘连蛋白在畸形血窦壁中的表达比正常中小静脉显著减少，分布类似。(4)VEGF在海绵状静脉畸形和小静脉的表达水平比中型静脉血管壁高，TGF-β_1表达在三者无明显差别，Ang-1在小静脉的表达水平最高。(5)神经纤维在畸形组织中分布很少。
第二军医大学硕士学位论文 中文摘要
结论 门）海绵状静脉畸形血窦壁中内皮细胞和平滑肌细胞发育不平衡，
平滑肌细胞表型异常，管壁薄弱，这是静脉畸形的主要病理结构基础。（2）IV型
胶原、纤维连接蛋白和层粘连蛋白低表达在畸形血窦壁异常结构形成中有重要作
用。门）海绵状静脉畸形血窦形成过程中存在血管塑型障碍，Aug八—Tie刁信号
传导通路缺陷参与了血管塑形障碍的发生。（4）畸形组织中神经纤维分布缺乏与
畸形发生发展之间有密切联系。
Objective To probe the pathogenesis of CVM of body surface on the basis of its
pathologic structure.(1) Observe the pathologic structure of CVM and study the
distribution and phenotype of EC and SMC in it.(3) Investigate the expression of the
structure protein and vascular groW-th factor in malfOrmation to probe the pathogenesis
of the abnormal sinusoid wall in it.(4) Investigate the nerve distribution in CVM and the
tissue around it to understand the relation between the nerve distribution and
malformation.
Method 42 specimens of CVM,l2 specimens of medium-sized vein and l2
specimens of small vein are included in our study.(1) H-E stain was used to observe the
pathologic structure of CVM,particulary the distribution of EC and SMC and calculate
the number of EC and SMC in the vessel wall of malformation and small veins.(2) 25
specimens of CVM and all specimens of medium-sized and small veins are selected for
immunohistochemistry stain with EnVision method.@ The monoclonal antibody anti
CD31 and Q -SMA which are the markers of EC and SMC are used for observing the
phenotype of these two kinds of cell.@ The monoclonal anibody anti N-Co1lagen,
Fibronectin and Laminin are used for investigating the expression of structure protein.
@ The monoclonal antibody ani VEGF, TGF-6, and Ang-1 are used for investigating
the expression of vascular groWth factor.@ The monoclonal antibody anti NSE and NF
are used for investigating the nerve distribution.
Result (l) The ratio of radius and thickness of cavemous venous mafformations is
higher obviously than moderate and small veins. The sinusoid wall does not increas its
thickness consistent with the expanding of lumen of sinusoid. (2) The ratio of ECs to
SMCs in malfOrmations is less obviously than in small veins, The expression of Q -
SMA in malformations is less obviously than in medium-sized and small veins,and the
organization is more confused;The expression of CD31 in them is similar.(3) The
expression of IV-Collagen, Fibronectin and Laxninin in CVM is less obviously than in
medium-sized and small veins,but the distribution is similar.(4) CVM and small veins
expressed VEGF stronger than medium-sizes veins .There is no difference in the
expression of TGF- 0,.The small veins express Ang-l strongest.(5) There is hardly no
nerve distribution in CVM.
-- 3 --
$=vkX%@tcF{4itx #x J%@
Conclusion (1) The EC and SMC in sinusoid wall of maIfOrmation develop
disproportionally and the SMCs have an abnormal phenotype,Which is the major
pathologic basis of CVM. (2) The low expression of IV-Collagen, Fibronectin and
Laminin playes important role in the pathogenesis of the abnorma1 sinusoid wall in
CVM.(4) There is disturbance of vascular remodelling in the development of sinusoid
wal1 in CVM,which may be caused by the defect of Ang-l-Tie-2 signal transduction
pathway. (5) The defect of nerve distribution in CVM have close relationship with the
occurrence and progress of CVM.
方法 挑选我院未经治疗单纯手术切除并经病理确诊的海绵状静脉畸形标本共42例；从其他手术中获取正常中型静脉和小静脉标本各12例。(1) 所有标本均行·HE染色，观察海绵状静脉畸形的病理结构，重点观察畸形血窦壁和正常小静脉壁中的内皮细胞和平滑肌细胞分布并计数。(2)选取25例海绵状静脉畸形标本以及正常中小静脉标本各12例，行EnVision法免疫组化染色。①用抗特异性内皮细胞抗原CD31和血管平滑肌细胞标志α-平滑肌肌动蛋白的单克隆抗体染色观察血窦壁内皮细胞和平滑肌细胞的表型。②应用抗Ⅳ型胶原、纤维连接蛋白和层粘连蛋白的单克隆抗体染色观察血管壁中结构蛋白表达。③应用抗血管内皮生长因子、转化生长因子-β_1以及血管生成素-1的单克隆抗体染色观察血管壁中血管形成因子表达。④应用抗神经元特异性烯醇化酶和神经微丝蛋白的单克隆抗体染色比较海绵状静脉畸形组织和正常中小静脉周围组织中神经纤维的分布。
结果 (1)海绵状静脉畸形血窦的血窦半径与血窦壁厚度的比例远大于正常中小静脉，畸形血窦腔扩大而血窦壁没有相应增厚。(2)畸形血窦壁中平滑肌细胞和内皮细胞的比例显著低于正常小静脉，α-SMA在畸形血窦的表达明显低于中小静脉，其排列紊乱，CD31表达相似。(3)Ⅳ型胶原、纤维连接蛋白和层粘连蛋白在畸形血窦壁中的表达比正常中小静脉显著减少，分布类似。(4)VEGF在海绵状静脉畸形和小静脉的表达水平比中型静脉血管壁高，TGF-β_1表达在三者无明显差别，Ang-1在小静脉的表达水平最高。(5)神经纤维在畸形组织中分布很少。
第二军医大学硕士学位论文 中文摘要
结论 门）海绵状静脉畸形血窦壁中内皮细胞和平滑肌细胞发育不平衡，
平滑肌细胞表型异常，管壁薄弱，这是静脉畸形的主要病理结构基础。（2）IV型
胶原、纤维连接蛋白和层粘连蛋白低表达在畸形血窦壁异常结构形成中有重要作
用。门）海绵状静脉畸形血窦形成过程中存在血管塑型障碍，Aug八—Tie刁信号
传导通路缺陷参与了血管塑形障碍的发生。（4）畸形组织中神经纤维分布缺乏与
畸形发生发展之间有密切联系。
Objective To probe the pathogenesis of CVM of body surface on the basis of its
pathologic structure.(1) Observe the pathologic structure of CVM and study the
distribution and phenotype of EC and SMC in it.(3) Investigate the expression of the
structure protein and vascular groW-th factor in malfOrmation to probe the pathogenesis
of the abnormal sinusoid wall in it.(4) Investigate the nerve distribution in CVM and the
tissue around it to understand the relation between the nerve distribution and
malformation.
Method 42 specimens of CVM,l2 specimens of medium-sized vein and l2
specimens of small vein are included in our study.(1) H-E stain was used to observe the
pathologic structure of CVM,particulary the distribution of EC and SMC and calculate
the number of EC and SMC in the vessel wall of malformation and small veins.(2) 25
specimens of CVM and all specimens of medium-sized and small veins are selected for
immunohistochemistry stain with EnVision method.@ The monoclonal antibody anti
CD31 and Q -SMA which are the markers of EC and SMC are used for observing the
phenotype of these two kinds of cell.@ The monoclonal anibody anti N-Co1lagen,
Fibronectin and Laminin are used for investigating the expression of structure protein.
@ The monoclonal antibody ani VEGF, TGF-6, and Ang-1 are used for investigating
the expression of vascular groWth factor.@ The monoclonal antibody anti NSE and NF
are used for investigating the nerve distribution.
Result (l) The ratio of radius and thickness of cavemous venous mafformations is
higher obviously than moderate and small veins. The sinusoid wall does not increas its
thickness consistent with the expanding of lumen of sinusoid. (2) The ratio of ECs to
SMCs in malfOrmations is less obviously than in small veins, The expression of Q -
SMA in malformations is less obviously than in medium-sized and small veins,and the
organization is more confused;The expression of CD31 in them is similar.(3) The
expression of IV-Collagen, Fibronectin and Laxninin in CVM is less obviously than in
medium-sized and small veins,but the distribution is similar.(4) CVM and small veins
expressed VEGF stronger than medium-sizes veins .There is no difference in the
expression of TGF- 0,.The small veins express Ang-l strongest.(5) There is hardly no
nerve distribution in CVM.
-- 3 --
$=vkX%@tcF{4itx #x J%@
Conclusion (1) The EC and SMC in sinusoid wall of maIfOrmation develop
disproportionally and the SMCs have an abnormal phenotype,Which is the major
pathologic basis of CVM. (2) The low expression of IV-Collagen, Fibronectin and
Laminin playes important role in the pathogenesis of the abnorma1 sinusoid wall in
CVM.(4) There is disturbance of vascular remodelling in the development of sinusoid
wal1 in CVM,which may be caused by the defect of Ang-l-Tie-2 signal transduction
pathway. (5) The defect of nerve distribution in CVM have close relationship with the
occurrence and progress of CVM.
引文
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75 Chaloupka JC,Vinuela F, Rober J,et al.An in vivo arteriovenous malformation model in swine:preliminary feasibility and natural history study. AJNR Am J Neuroradiol 1994 May;15(5):945-50.
76 Massoud Tf, Vinueta F, Ji C,et al.An experimental arteriovenous malformation model in swine:anatomic basis and constructive technique. AJNR Am J Neuroradiol 1994 Sep; 15(8):1537-45.
77 Massoud TF, Vinters AV, Chao Rh,et al.Histopathologic characteristics of a chronic arteriovenous malformation in a swine model:preliminary study. AJNR Am J Neuroradiol 2000 Aug;21(7):1268-76.
78 Massoud TF, Ji C,Vinuela F, et al. Labortory simulations and training in endovascular embolotherapy with a swine arteriovenous malformation model. V 1996 Feb;17(2):271-9
79 王大明，凌峰，李萌，等．脑动静脉畸形动物模型的初步建立．中华神经外科杂志，1997，13(6)：235-237
80 Qian Z,Climent S,Maynar M,et al.A simplified arteriovenous malformation model in sheep:feability study. AJNR Am J Neuroradiol 1999 May;20(5):765-70.
81 Siekmann K, Wakhlao AK,Lieber BB,et al. Modification of a previously described arteriovenous malformation model in swine:endovascular and combined surgical/endovascular construction and hemodynamics. AJNR Am J Neuroradiol 2000 Oct;21(9):1722-5.
82 Kerber CW, Flaherty LW.A teaching and research simulator for therapeutic and embolization. AJNR Am J Neuroradol, 1980,1:167-176.
83 Kerber CW, Hecht ST, Knox K. Arteriovenous malformation model for training and research. ANJR Am J Neuroradol, 1997,18:1229-32
84 Park S,Yoon H,Suh DC,et al. An arteriovenous malformation model for testing liquid embolic materials. ANJR Am J Neuroradol, 1997,18:1892-96
85 Hecht ST, Horton JA,Kerber CW. Hemodynamic of the central nervous system arteriovenous malformation nidus during particular embolization.Neuroradiology, 1991,33:62-4.
86 Kailasnath P, Chaloupka JC.Mathematical modeling of AVM physiology using conpartmental network analysis: theoretical consideratios and preliminary in vivo validation using a previously diveloped animal model.Neurol Res 1996 Aug;18(4):361-6.
87 Hademenos GJ,Massoud TF, Vinuela F.A biomathematical model of intracranial arteriovenous malformations based on electrical network analysisaa:theory and hemodynamics.Neurosurgery 1996 May;38(5): 1005-14,discussion 1014-5.
88 Hademenos GJ, Massoud TF. An electrical network model of intracranial arteriovenous: analusis of variations in hemodynamics and biophysical parameters.Neurol Res 1996 Dec;18(6):575-89.
89 Hademenos GJ,Massoud TF. Risk of intracranial arterioenous malformation rupture clue to venous drainage impairment,A theoretical analysis. Stroke 1996 Jun;27(6):1072-83
90 Massoud TF, Hademenos GJ,Young WL,et al. Can induction of systemic hypotenion help prevent nidus rupture complicating arteriovenous malformation emboliation?analysis of underlying mechanism achieved using a theoretical model. AJNR Am J Neuroradiol 2000 Aug;21(7):1255-67.
91 Gao E,Young Wl,Ornstein E,et al.A theoretical model of cerebral hemodymics:application to the study of arteriovenous malformations. J Cereb Blood Flow Metab 1997 Aug:17(8):905-18.
92 Gao E, Young WL,Pile-Spellman,et al.Cerebral arteriovenous malformation feeding artery aneurysms:a theoretical model of intravascular pressure changs after treament. Neurosurgery 1997 Dec;41(6):1345-56,discussion 1556-8.
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74 Lemson MS,Daemen MJ,Kitslaar PJ,et al.A new animal model to study intimal hyperplasia in arteriovenous fistulas. J Surg Res 1999 Jul;85(1):51-8.
75 Chaloupka JC,Vinuela F, Rober J,et al.An in vivo arteriovenous malformation model in swine:preliminary feasibility and natural history study. AJNR Am J Neuroradiol 1994 May;15(5):945-50.
76 Massoud Tf, Vinueta F, Ji C,et al.An experimental arteriovenous malformation model in swine:anatomic basis and constructive technique. AJNR Am J Neuroradiol 1994 Sep; 15(8):1537-45.
77 Massoud TF, Vinters AV, Chao Rh,et al.Histopathologic characteristics of a chronic arteriovenous malformation in a swine model:preliminary study. AJNR Am J Neuroradiol 2000 Aug;21(7):1268-76.
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79 王大明，凌峰，李萌，等．脑动静脉畸形动物模型的初步建立．中华神经外科杂志，1997，13(6)：235-237
80 Qian Z,Climent S,Maynar M,et al.A simplified arteriovenous malformation model in sheep:feability study. AJNR Am J Neuroradiol 1999 May;20(5):765-70.
81 Siekmann K, Wakhlao AK,Lieber BB,et al. Modification of a previously described arteriovenous malformation model in swine:endovascular and combined surgical/endovascular construction and hemodynamics. AJNR Am J Neuroradiol 2000 Oct;21(9):1722-5.
82 Kerber CW, Flaherty LW.A teaching and research simulator for therapeutic and embolization. AJNR Am J Neuroradol, 1980,1:167-176.
83 Kerber CW, Hecht ST, Knox K. Arteriovenous malformation model for training and research. ANJR Am J Neuroradol, 1997,18:1229-32
84 Park S,Yoon H,Suh DC,et al. An arteriovenous malformation model for testing liquid embolic materials. ANJR Am J Neuroradol, 1997,18:1892-96
85 Hecht ST, Horton JA,Kerber CW. Hemodynamic of the central nervous system arteriovenous malformation nidus during particular embolization.Neuroradiology, 1991,33:62-4.
86 Kailasnath P, Chaloupka JC.Mathematical modeling of AVM physiology using conpartmental network analysis: theoretical consideratios and preliminary in vivo validation using a previously diveloped animal model.Neurol Res 1996 Aug;18(4):361-6.
87 Hademenos GJ,Massoud TF, Vinuela F.A biomathematical model of intracranial arteriovenous malformations based on electrical network analysisaa:theory and hemodynamics.Neurosurgery 1996 May;38(5): 1005-14,discussion 1014-5.
88 Hademenos GJ, Massoud TF. An electrical network model of intracranial arteriovenous: analusis of variations in hemodynamics and biophysical parameters.Neurol Res 1996 Dec;18(6):575-89.
89 Hademenos GJ,Massoud TF. Risk of intracranial arterioenous malformation rupture clue to venous drainage impairment,A theoretical analysis. Stroke 1996 Jun;27(6):1072-83
90 Massoud TF, Hademenos GJ,Young WL,et al. Can induction of systemic hypotenion help prevent nidus rupture complicating arteriovenous malformation emboliation?analysis of underlying mechanism achieved using a theoretical model. AJNR Am J Neuroradiol 2000 Aug;21(7):1255-67.
91 Gao E,Young Wl,Ornstein E,et al.A theoretical model of cerebral hemodymics:application to the study of arteriovenous malformations. J Cereb Blood Flow Metab 1997 Aug:17(8):905-18.
92 Gao E, Young WL,Pile-Spellman,et al.Cerebral arteriovenous malformation feeding artery aneurysms:a theoretical model of intravascular pressure changs after treament. Neurosurgery 1997 Dec;41(6):1345-56,discussion 1556-8.