Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases
Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases
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DOI：
10.1002/hep.21143
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发表时间：
2006-05-01
期刊：
影响因子：
13.5
通讯作者：
Strazzabosco, M
中科院分区：
文献类型：
--
作者：
Fabris, L;Cadamuro, M;Strazzabosco, M
常染色体显性多囊肾病（ADPKD）累及肝脏的特征是胚胎导管板（DP）重塑改变，伴有胆道囊肿和门静脉系统异常。导致ADPKD的遗传缺陷已被确定，但肝囊肿生长的机制仍不确定。为了探讨血管生成机制的可能作用，我们研究了血管内皮生长因子（VEGF）、血管生成素-1 （Ang-1）、血管生成素-2 （Ang-2）及其受体（VEGFR-1、VEGFR-2、Tie-2）在ADPKD、Caroli病、正常肝脏和胎儿肝脏中的免疫组织化学表达。实时荧光定量pcr检测ADPKD和对照肝脏中Ang-1和Ang-2基因的表达。采用PCNA Western Blot对离体大鼠胆管细胞进行检测，对ADPKD患者及ADPKD小鼠模型（Pkd2(WS25/-)）培养的胆管细胞进行NITS检测，研究VEGF对胆管细胞增殖的影响。ADPKD和Caroli的胆管细胞中VEGF、VEGFR-1、VEGFR-2和Ang-2呈强阳性，ADPKD中Ang-1和Tie-2呈强阳性，与胎儿导管板细胞相似。VEGF刺激了正常和ADPKD胆管细胞的增殖，但在后者中效果尤为明显。单独使用Ang-1对VEGF无影响，但有协同作用。VEGF在胆管细胞上的表达与微血管密度呈正相关。综上所述，多囊性肝病的胆管细胞中VEGF、VEGFRs、Ang-1和Tie-2的表达强烈上调，与囊上皮的不成熟表型一致。VEGF和Ang-1对胆管细胞生长有自分泌增殖作用，对门静脉系统有旁分泌作用，从而促进囊肿的生长和血管供应。
Liver involvement in autosomal dominant polycystic kidney disease (ADPKD) is characterized by altered remodeling of the embryonic ductal plate (DP) with presence of biliary cysts and aberrant portal vasculature. The genetic defect causing ADPKD has been identified, but mechanisms of liver cyst growth remain uncertain. To investigate the possible role of angiogenic mechanisms, we have studied the immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their receptors (VEGFR-1, VEGFR-2, Tie-2) in ADPKD, Caroli's disease, normal and fetal livers. In ADPKD and control livers Ang-1 and Ang-2 gene expression was studied by real-time-PCR. Effects of VEGF on cholangiocyte proliferation were studied by PCNA Western Blot in isolated rat cholangiocytes and by NITS assay in cultured cholangiocytes isolated from ADPKD patients and from an ADPKD mouse model (Pkd2(WS25/-)). Cholangiocytes were strongly positive for VEGF, VEGFR-1, VEGFR-2 and Ang-2 in ADPKD and Caroli, and also for Ang-1 and Tie-2 in ADPKD, similar to fetal ductal plate cells. VEGF stimulated proliferation in both normal and ADPKD cholangiocytes, but the effect was particularly evident in the latter. Ang-1 alone had no effect, but was synergic to VEGF. VEGF expression on cholangiocytes positively correlated with microvascular density. In conclusion, consistent with the immature phenotype of the cystic epithelium, expression of VEGF, VEGFRs, Ang-1 and Tie-2 is strongly upregulated in cholangiocytes from polycystic liver diseases. VEGF and Ang-1 have autocrine proliferative effect on cholangiocyte growth and paracrine effect on portal vasculature, thus promoting the growth of the cysts and their vascular supply.