發(fā)布時(shí)間：2018-07-12 12:31

  本文選題：血流動(dòng)力學(xué) + 顱內(nèi)動(dòng)脈瘤　； 參考：《第二軍醫(yī)大學(xué)》2014年博士論文

【摘要】：第一部分 血流動(dòng)力學(xué)誘導(dǎo)兔基底動(dòng)脈頂端動(dòng)脈瘤樣重構(gòu)及機(jī)制 目的：顱內(nèi)動(dòng)脈瘤是危害性極大的腦血管疾病，但具體生成機(jī)制仍不明確。本研究通過改變血流動(dòng)力學(xué)，誘導(dǎo)兔基底動(dòng)脈頂端動(dòng)脈瘤樣重構(gòu)并探討可能的機(jī)制。 方法：新西蘭大白兔36只，分3組，假手術(shù)組12只，術(shù)后1w組12只，術(shù)后2w組12只。術(shù)前即刻及術(shù)后1w、2w，分別行TOF法MRA檢查及血流動(dòng)力學(xué)分析。在術(shù)后1w、2w，處死兔子，動(dòng)脈灌注，解剖出基底動(dòng)脈頂端，縱向切片。病理切片分別行Masson，EVG染色，分別觀察平滑肌及內(nèi)彈力層及抗-RAM11（巨噬細(xì)胞），抗-eNOS、抗-iNOS（內(nèi)皮細(xì)胞標(biāo)志物），抗-NF-κB p65、抗-TNF-α（促炎因子）免疫組化染色和抗-α-SMA（平滑肌收縮蛋白）、抗-MMP-2、抗-MMP-9（細(xì)胞外基質(zhì)降解酶）免疫熒光染色�；讋�(dòng)脈頂端組織分別采取ELISA法檢測(cè)NF-κB、TNF-α蛋白相對(duì)含量，實(shí)時(shí)定量PCR法檢測(cè)CD68、eNOS、iNOS、α-SMA、MMP-2、MMP-9mRNA含量。 結(jié)果：雙側(cè)頸總動(dòng)脈結(jié)扎后83.3%（10/12）基底動(dòng)脈頂端壁面切應(yīng)力升高，誘導(dǎo)頂端內(nèi)彈力層變薄、斷裂或缺失，平滑肌層變薄弱，并瘤壁向外突出，形成動(dòng)脈瘤樣改變。但兩實(shí)驗(yàn)組各有一只動(dòng)物（16.7%（2/12））基底動(dòng)脈頂端壁面切應(yīng)力較其他動(dòng)物低，且基底動(dòng)脈頂端未出現(xiàn)動(dòng)脈瘤樣改變。在重構(gòu)的基底動(dòng)脈中，三組之間內(nèi)彈力層缺失長(zhǎng)度、中膜變薄長(zhǎng)度及中膜薄弱百分比有顯著統(tǒng)計(jì)學(xué)差異(P 0.001，，P0.001，P 0.001)。基底動(dòng)脈頂端動(dòng)脈瘤樣重構(gòu)區(qū)域未見巨噬細(xì)胞浸潤。血流動(dòng)力學(xué)改變導(dǎo)致血管內(nèi)皮細(xì)胞功能障礙，血管保護(hù)性因子eNOS分泌減少，而具有血管毒性作用的iNOS分泌增加，三組之間eNOS mRNA、iNOS mRNA表達(dá)有統(tǒng)計(jì)學(xué)差異（P=0.003，P=0.019）。血流動(dòng)力學(xué)及細(xì)胞因子作用導(dǎo)致血管平滑肌細(xì)胞表型轉(zhuǎn)化，收縮型細(xì)胞減少，促炎、促基質(zhì)重構(gòu)型細(xì)胞增多，三組α-SMA mRNA表達(dá)有統(tǒng)計(jì)學(xué)差異（P 0.001）。合成型平滑肌細(xì)胞通過分泌MMPs及使TNF-α表達(dá)增高，NF-κB激活，降解細(xì)胞外基質(zhì)，損傷血管壁，導(dǎo)致管壁變薄、向外突出，三組之間有統(tǒng)計(jì)學(xué)差異（P 0.001，P 0.001，P 0.001）。 結(jié)論：?jiǎn)渭兓讋?dòng)脈血流動(dòng)力學(xué)改變，導(dǎo)致基底動(dòng)脈頂端壁面切應(yīng)力升高，出現(xiàn)動(dòng)脈瘤樣病理重構(gòu)。壁面切應(yīng)力較低的動(dòng)物未誘導(dǎo)出動(dòng)脈瘤樣改變。這些動(dòng)脈瘤樣重構(gòu)不是炎癥細(xì)胞引起的炎癥反應(yīng)，而是血流動(dòng)力學(xué)改變導(dǎo)致血管內(nèi)皮細(xì)胞功能障礙，血管保護(hù)性因子eNOS分泌減少，而血管毒性作用的iNOS分泌增加、血管平滑肌細(xì)胞表型轉(zhuǎn)化，大量促炎因子分泌增加及細(xì)胞外基質(zhì)降解等，一系列生物力學(xué)反應(yīng)過程。 第二部分 血流動(dòng)力學(xué)誘導(dǎo)兔基底動(dòng)脈干血管重構(gòu)及其影響 目的：血管重構(gòu)在血管性疾病發(fā)揮重要作用。本研究通過新西蘭大白兔雙側(cè)頸總動(dòng)脈結(jié)扎，觀察基底動(dòng)脈干血管重構(gòu)及其對(duì)基底動(dòng)脈頂端的影響。 方法：新西蘭大白兔18只，假手術(shù)組6只，實(shí)驗(yàn)組術(shù)后1w6只，實(shí)驗(yàn)組術(shù)后2w6只。術(shù)前、術(shù)后1d、1w、2w，經(jīng)顱多普勒測(cè)定基底動(dòng)脈血流速度。術(shù)前即刻及術(shù)后1w、2w，分別行TOF法MRA檢查并血管重建及計(jì)算血流動(dòng)力學(xué)。所有兔子術(shù)后1w、2w分別行腦血管造影并分別測(cè)量分析血管直徑、彎曲角度、彎曲指數(shù)。每組動(dòng)物分別于術(shù)后1w、2w取出基底動(dòng)脈，橫斷面切片，Masson、EVG染色及免疫組化染色。對(duì)壁面切應(yīng)力較低動(dòng)物基底動(dòng)脈頂端行縱形切片及HE染色。 結(jié)果：雙側(cè)頸總動(dòng)脈結(jié)扎后，在每個(gè)時(shí)間點(diǎn)基底動(dòng)脈血流速度較假手術(shù)組均明顯加快，兩組之間血流速度有顯著統(tǒng)計(jì)學(xué)差異(P 0.001)�；讋�(dòng)脈壁面切應(yīng)力自匯合部開始明顯上升，至中部有所下降但仍高于假手術(shù)組；但術(shù)后1w、2w組各有一只動(dòng)物壁面切應(yīng)力低于同組其他動(dòng)物。實(shí)驗(yàn)組術(shù)后基底動(dòng)脈中部開始彎曲，術(shù)后2w基底動(dòng)脈管腔向外擴(kuò)張且彎曲成角更明顯；但彎曲越明顯，基底動(dòng)脈頂端壁面切應(yīng)力越低。血管造影顯示基底動(dòng)脈向外擴(kuò)張并彎曲成角，假手術(shù)組、實(shí)驗(yàn)組術(shù)后1w、2w之間基底動(dòng)脈直徑、彎曲角度和彎曲指數(shù)有顯著統(tǒng)計(jì)學(xué)差異(P 0.001，P=0.008，P 0.001)。且基底動(dòng)脈直徑越大，壁面切應(yīng)力越低�；讋�(dòng)脈病理切片染色顯示，實(shí)驗(yàn)組基底動(dòng)脈直徑較假手術(shù)組大；實(shí)驗(yàn)組內(nèi)彈力層鋸齒狀皺褶拉伸變平，部分平滑肌層遷移入內(nèi)膜；實(shí)驗(yàn)組術(shù)后1w平滑肌層較假手術(shù)組略有增生，術(shù)后2w有所減少。HE染色顯示16.7%（2/12）基底動(dòng)脈中段壁面切應(yīng)力較低動(dòng)物基底動(dòng)脈尖未見動(dòng)脈瘤樣重構(gòu)。免疫組化染色顯示三組eNOS均表達(dá)，實(shí)驗(yàn)組術(shù)后1w、2w增多；假手術(shù)組iNOS不表達(dá)，實(shí)驗(yàn)組表達(dá)增多；術(shù)后1w組MMP-2、MMP-9表達(dá)增多，術(shù)后2w時(shí)表達(dá)減少。 結(jié)論：雙側(cè)頸總動(dòng)脈結(jié)扎后，基底動(dòng)脈血流速度加快，83.3%（10/12）壁面切應(yīng)力升高，導(dǎo)致兔基底動(dòng)脈發(fā)生病理重構(gòu)，管腔擴(kuò)張并彎曲成角。16.7%基底動(dòng)脈擴(kuò)張及彎曲顯著，導(dǎo)致壁面切應(yīng)力降低，基底動(dòng)脈頂端未出現(xiàn)動(dòng)脈瘤樣重構(gòu)。病理染色示內(nèi)彈力層完整，鋸齒狀拉伸，平滑肌層變薄弱并遷移入內(nèi)膜。NO信號(hào)通路及MMP-2、MMP-9參與了基底動(dòng)脈血管重構(gòu)。
[Abstract]:Part one
Hemodynamics induced aneurysm like remodeling in the top of the basilar artery in rabbits and its mechanism
Objective: intracranial aneurysm is a very dangerous cerebrovascular disease, but the specific mechanism is still unclear. This study induced the remodeling of the aneurysm like the apical artery of the basilar artery in rabbits and explored the possible mechanism by changing the hemodynamics.
Methods: 36 New Zealand white rabbits were divided into 3 groups, 12 sham operation groups, 12 1W after operation and 12 in group 2W after operation. MRA examination and hemodynamic analysis were performed immediately before operation and 1W, 2W after operation. After operation, 1W, 2W, rabbits were executed and arterial perfusion, and the apical and longitudinal sections of the basilar artery were dissected. Masson, EVG staining, respectively, were observed, respectively. The pathological sections were stained respectively to view the pathological sections respectively. The pathological sections were stained respectively, respectively, to observe the pathological sections, respectively. Inspection of smooth muscle and internal elastic layer and anti -RAM11 (macrophage), anti -eNOS, anti -iNOS (endothelial cell marker), anti -NF- kappa B p65, anti -TNF- alpha (pro-inflammatory factor) immuno histochemical staining and anti a -SMA (smooth muscle contractile protein), anti -MMP-2, anti -MMP-9 (extracellular matrix degrading enzyme) immunofluorescence staining. The apical tissue of basilar artery took ELISA method. The relative content of NF- kappa B and TNF- alpha protein was detected. CD68, eNOS, iNOS, alpha -SMA, MMP-2 and MMP-9mRNA contents were detected by real-time quantitative PCR.
Results: 83.3% (10/12) basilar artery apical wall shear stress increased after bilateral common carotid artery ligation. The elastic layer in the top of the basilar artery was thinner, broken or missing, the smooth muscle layer became weak, and the wall of the tumor protruded out to form an aneurysm like change. But the two experimental group had each animal (16.7% (2/12)) of the basilar artery wall shear stress compared with the other animals. There was no aneurysmal change at the top of the basilar artery. In the reconstructed basilar artery, the length of the inner elastic layer, the thinning length of the middle membrane and the weak percentage of the middle membrane were statistically significant differences (P 0.001, P0.001, P 0.001). Vascular endothelial cell dysfunction, vascular protective factor eNOS secretion decreased, and vascular toxic effect of iNOS secretion increased, between the three groups of eNOS mRNA, iNOS mRNA expression is statistically significant (P=0.003, P=0.019). Hemodynamic and cytokine effects lead to the vascular smooth muscle cell phenotype transformation, contractile type cell reduction, proinflammatory The expression of matrix remodeling type cells increased and the expression of alpha -SMA mRNA in the three group was statistically different (P 0.001). The synthetic smooth muscle cells were activated by MMPs and TNF- alpha expression, NF- kappa B was activated, the extracellular matrix was degraded and the vascular wall was damaged. The wall of the tube became thinner and outbound, and there were statistical differences between the three groups (P 0.001, P 0.001, P 0.001).
Conclusion: the changes in the basilar artery hemodynamics lead to the increase of the wall shear stress at the top of the basilar artery and the pathological remodeling of the aneurysm. The animals with lower wall shear stress do not induce the changes of the aneurysm like changes. These aneurysmal remodeling is not an inflammatory reaction caused by inflammatory cells, but the hemodynamic changes lead to the vascular endothelium. Cell dysfunction, vascular protective factor eNOS secretion decreased, and vascular toxic effect of iNOS secretion increased, vascular smooth muscle cell phenotype transformation, a large number of proinflammatory cytokines secretion increase and extracellular matrix degradation, a series of biomechanical reactions.
The second part
Hemodynamic remodeling of basilar artery in rabbits and its influence
Objective: vascular remodeling plays an important role in vascular diseases. This study was conducted by ligating bilateral common carotid artery in New Zealand white rabbits to observe the revasculature of the basilar artery and its effect on the top of the basilar artery.
Methods: 18 New Zealand white rabbits and 6 sham operation group, 1w6 only in experimental group, 2w6 only after operation in experimental group. Before operation, 1D, 1W, 2W, and transcranial Doppler were used to determine the velocity of basilar artery blood flow. Preoperative and postoperative 1W, 2W, TOF method MRA examination, vascular reconstruction and hemodynamics were performed respectively. All rabbits were performed cerebrovascular angiography and 2W after operation, respectively. The diameter of blood vessel, bending angle and bending index were measured and analyzed respectively. The basilar artery was taken out of 1W, 2W after operation, cross section section, Masson, EVG staining and immunohistochemical staining. The longitudinal section and HE staining were performed on the top of the basilar artery at the lower wall shear stress.
Results: after the ligation of bilateral common carotid artery, the velocity of basilar artery blood flow at each time point was significantly faster than that in the sham operation group, and the velocity of blood flow was significantly different between the two groups (P 0.001). The wall shear stress of the basilar artery began to rise obviously from the confluence part, to the middle of the middle, but still higher than that in the sham operation group; but after the operation, the group of 1W and 2W had each group. The wall shear stress of one animal was lower than that of the other animals. The central basilar artery in the experimental group began to bend after the operation, and the basilar artery cavity expanded outward and the curved angle was more obvious after the operation, but the more obvious the bending, the lower the wall shear stress of the basilar artery was lower. The angiography showed that the basal artery of the basilar artery was dilated and curved into the angle, the sham operation group, the experiment showed the 2W. The basilar artery diameter, bending angle and bending index between 1W and 2W after operation were significantly different (P 0.001, P=0.008, P 0.001). The larger the diameter of the basilar artery, the lower the wall shear stress. The basilar artery diameter in the basilar artery showed that the diameter of the basilar artery in the experimental group was larger than that in the artificial hand, and the stretch of the serrated fold in the elastic layer in the experimental group was leveled. In the experimental group, the 1W smooth muscle layer was slightly proliferated in the experimental group than the sham operation group. After the operation, the 2W decreased by.HE staining and showed 16.7% (2/12) the middle basilar artery wall shear stress in the middle basilar artery was lower than that of the basilar artery. The immunohistochemical staining showed that all the three groups of eNOS were expressed, and the 1W and 2W increased after operation in the experimental group. In the sham operation group, iNOS was not expressed, and the expression of the experimental group increased. After operation, the expression of MMP-2 and MMP-9 in group 1W increased, and the expression of 2W decreased after operation.
Conclusion: after the ligation of bilateral common carotid artery, the velocity of the basilar artery is accelerated and the wall shear stress of 83.3% (10/12) increases, causing pathological remodeling of the basilar artery in the rabbit, dilation of the basilar artery and the dilatation and bending of the.16.7% basilar artery, which leads to the decrease of the wall shear stress and no aneurysm like reconstruction at the top of the basilar artery. Pathological staining shows that the artery of basilar artery is not reconstructed. The inner elastic layer is complete, zigzag stretch, smooth muscle layer becomes weak and migration into the intimal.NO signaling pathway and MMP-2, MMP-9 participates in basilar artery remodeling.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R743

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9 張p

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