Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis
Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis
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DOI：
10.1016/s0046-8177(03)00245-4
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发表时间：
2003-08-01
期刊：
影响因子：
3.3
通讯作者：
Satta, J
中科院分区：
文献类型：
--
作者：
Soini, Y;Salo, T;Satta, J
血管生成不仅在胚胎发生中是一个重要的生物学过程，而且在几种主要疾病（包括癌症、糖尿病和炎症）的进展中也是一个重要的生物学过程。过度血管化也可能导致某些心血管疾病，如动脉粥样硬化，但关于其对主动脉瓣狭窄的影响，仍然存在相互矛盾的报道。采用免疫组织化学技术，我们评估了血管密度和分布的血管生成（FVIII）和血管内皮生长因子（VEGF）的表达，以及表达的2个VEGF受体，Flt-1和Flk-1，在55个非风湿性和6个对照主动脉瓣。鉴于VEGF的血管生成作用是由一氧化氮的持续形成介导的事实，还用3种一氧化氮合酶（eNOS、iNOS和nNOS）抗体对样品进行免疫染色。VEGF及其受体的免疫组化结果通过免疫印迹技术进行验证。中度瓣膜狭窄患者的血管密度最高，病变瓣膜中FVIII阳性血管的平均数量为1.7 ± 1.9条/mm 2，而正常瓣膜中不含血管。慢性炎症组血管密度明显增高（P = 0.007）。有趣的是，接受他汀类药物治疗的患者血管密度显著低于未接受此类治疗的患者（P = 0.001）。瓣膜显示出明显的VEGF、Flt-1、Flk-1和eNOS阳性的活化内皮细胞、间质梭形肌纤维母细胞和组织细胞。与此相反，iNOS和nNOS的免疫反应，只看到在非内皮基质细胞，他们的表达较弱。血管密度增加与Flk-1表达增加（内皮细胞P = 0.028，基质细胞P = 0.009）和内皮eNOS表达增加（P 0.024）显著相关。VEGF也观察到类似的趋势，但Flt-1没有。我们的研究结果表明，在非风湿性主动脉瓣狭窄中存在明显的血管生成反应和血管生成因子，这表明血管生成可能会影响这种疾病的演变。第34卷：756-763。(C)2003年爱思唯尔公司All rights reserved.
Angiogenesis is an essential biological process not only in embryogenesis, but also in the progression of several major diseases, including cancer, diabetes, and inflammation. Excessive vascularization can also contribute to some cardiovascular pathologies, such as atherosclerosis, but contradictory reports still prevail regarding its impact on aortic stenosis. Using immunohistochemical techniques, we assessed the vascular density and distribution of angiogenesis (FVIII) and vascular endothelial growth factor (VEGF) expression as well as the expression of 2 VEGF receptors, Flt-1 and Flk-1, in 55 nonrheumatic and 6 control aortic valves. In the light of the fact that the angiogenic effect of VEGF is mediated by sustained formation of nitric oxide, the samples were also immunostained with 3 nitric oxide synthase (eNOS, iNOS, and nNOS) antibodies. The immunohistochemical findings of VEGF and its receptors were verified by immunoblotting techniques. Vascular density was highest in the cases with moderate valve stenosis, and the mean number of FVIII-positive blood vessels was 1.7 +/- 1.9 vessels/mm(2) in the diseased valves, whereas the normal valves contained no blood vessels. Vascular density was significantly higher in the cases showing chronic inflammation (P = 0.007). Interestingly, the patients receiving statin therapy had significantly lower vascular densities than those not receiving such therapy (P = 0.001). Diseased valves showed distinct VEGF, Flt-1, Flk-1, and eNOS positivity of activated endothelial, stromal fusiform myofibroblastic, and histocytic cells. In contrast, immunoreactivity for iNOS and nNOS was seen only in nonendothelial stromal cells, and their expression was weaker. Enhanced vascular density was significantly associated with increased expression of Flk-1 (P = 0.028 for endothelial and P = 0.009 for stromal cells) and with endothelial eNOS expression (P 0.024). A similar tendency was also observed for VEGF, but not for Flt-1. Our results show a distinct angiogenic response and the presence of angiogenic factors in nonrheumatic aortic valve stenosis, suggesting that angiogenesis may influence on the evolution of this disease. Hum PATHOL 34:756-763. (C) 2003 Elsevier Inc. All rights reserved.