Retinoblastoma protein: a molecular regulator of chronic venous insufficiency.
Retinoblastoma protein: a molecular regulator of chronic venous insufficiency.
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DOI：
10.1006/jsre.1998.5310
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发表时间：
1998-05
期刊：
影响因子：
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通讯作者：
P. Pappas;G. Gwertzman;D. Defouw;F. Padberg;M. B. Silva;W. Durán;R. Hobson
中科院分区：
文献类型：
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作者：
P. Pappas;G. Gwertzman;D. Defouw;F. Padberg;M. B. Silva;W. Durán;R. Hobson
目的慢性静脉功能不全（CVI）和静脉曲张（VV）形成的组织学特征是平滑肌细胞（SMC）由收缩型转化为分泌型和胶原蛋白大量沉积。这些过程的亚细胞调节点可能是视网膜母细胞瘤蛋白（pRb），一种已知的细胞增殖抑制剂和分化调节剂。我们假设pRb磷酸化与VV形成相关，并作为一种可能的亚细胞调节因子发挥作用。方法将患者分为两组。第1组（n = 6）由接受冠状动脉旁路移植术患者的静脉标本组成。第2组（n = 6）包括症状性CVI患者和需要GSV剥脱术的经多普勒证实的大隐静脉（GSV）狭窄。用抗人pRb单克隆抗体对GSV蛋白提取物进行Western印迹，并测定非磷酸化和磷酸化pRb的程度。使用条带强度（计算机校准的强度单位）的图像分析来量化结果。电镜观察两组平滑肌细胞超微结构及静脉壁结构。结果静脉曲张组pRb蛋白磷酸化强度为523 ± 188单位，正常组pRb蛋白磷酸化强度为153 ± 41单位（P < 0.05）。曲张GSV中的SMC被紊乱的胶原沉积物包围，并显示具有球形空泡细胞的分泌表型。正常GSV的平滑肌细胞呈纺锤形，具有收缩性表型和结构良好的细胞外基质。结论CVI患者VV的形成与pRb磷酸化及平滑肌细胞由收缩型向分泌型转变有关。这些数据表明，SMC去分化调节pRb和这种蛋白质（磷酸化）的去抑制可能是一个重要的因素，在下肢静脉曲张的发展。
PURPOSE Chronic venous insufficiency (CVI) and varicose vein (VV) formation is characterized histologically by the transformation of smooth muscle cells (SMC) from a contractile to a secretory phenotype and by intense collagen deposition. The subcellular regulation point for these processes may be the retinoblastoma protein (pRb), a known inhibitor of cellular proliferation and regulator of differentiation. We hypothesize that pRb phosphorylation is associated with VV formation and functions as a possible subcellular regulator. METHODS Patients were separated into two groups. Group 1 (n = 6) consisted of vein specimens obtained from patients undergoing coronary artery bypass grafting. Group 2 (n = 6) consisted of patients with symptomatic CVI and duplex confirmed refluxing greater saphenous veins (GSVs) who required GSV stripping. Western blots of GSV protein extracts were performed with anti-human pRb monoclonal antibodies and the degree of nonphosphorylated and phosphorylated pRb was determined. Results were quantified using image analysis of band intensities (computer calibrated intensity units). The ultrastructural appearance of SMCs and the vein wall architecture were qualitatively analyzed with electron microscopy in both groups. RESULTS Phosphorylated pRb from varicose GSVs exhibited intensities of 523 +/- 188 units, while phosphorylated pRb from normal GSVs demonstrated intensities of 153 +/- 41 units (P < 0.05). SMCs in varicosed GSVs were surrounded by disorganized collagen deposits and displayed a secretory phenotype with spherical vacuolated cells. SMCs from normal GSVs appeared spindle shaped with a purported contractile phenotype and a well-structured extracellular matrix. CONCLUSION Our data demonstrate that VV formation, in patients with CVI, is associated with phosphorylated pRb and the transformation of SMCs from a contractile to a secretory ultrastructural morphology. The data suggest that SMC dedifferentiation is regulated by pRb and the disinhibition of this protein (phosphorylation) may be an significant factor in the development of lower extremity varicosities.