Acute intravesical infusion of a cobalt solution stimulates a hypoxia response, growth and angiogenesis in the rat bladder
Acute intravesical infusion of a cobalt solution stimulates a hypoxia response, growth and angiogenesis in the rat bladder
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DOI：
10.1097/01.ju.0000058406.16931.93
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发表时间：
2003-06-01
影响因子：
6.6
通讯作者：
Levin, RM
中科院分区：
文献类型：
--
作者：
Buttyan, R;Chichester, P;Levin, RM
目的：实验性部分膀胱出口梗阻诱导大鼠膀胱生长和重塑过程与人良性前列腺增生相似。先前我们提出膀胱缺氧与部分膀胱出口梗阻是膀胱生长过程的刺激因素。我们报告了一种简单的化学试剂（钴离子）在大鼠膀胱中模拟缺氧的急性效应的测试结果。我们测量了其影响膀胱基因表达、血管生成和生长过程的能力。材料与方法：将成年大鼠分为两组。一组（对照组）连续6天灌胃生理盐水3次，每次30分钟，另一组灌胃生理盐水100mum。同时得到CoCl2。所有动物也通过植入渗透泵连续输注BrdU 6天。将这些大鼠的膀胱部分固定、切片、染色进行显微镜分析和免疫组织化学染色，通过因子VIII染色鉴定BrdU阳性细胞和血管元件。其余部分冷冻提取蛋白，对比分析蛋白在Western blots上缺氧诱导因子-1 α和血管内皮生长因子的表达。结果：CoCl2输注后膀胱粘膜下区广泛扩张，与生理盐水输注后膀胱差异有统计学意义。在这个扩大区域的细胞以及尿路上皮内的细胞被发现广泛地标记了BrdU，而对照膀胱在任何区域都很少有BrdU标记的细胞。因子VIII免疫组化分析显示，钴处理大鼠粘膜下区域含有大量的小血管和微血管，而对照组不明显。这些细胞变化与我们的发现一致，与对照组相比，钴处理膀胱中缺氧诱导因子-1 α和血管内皮生长因子蛋白表达增加。结论：急性膀胱内注入钴离子溶液可引起大鼠膀胱缺氧反应，并增加膀胱血管生成和生长。这一发现支持了缺氧是部分膀胱出口梗阻后膀胱生长的刺激因素的观点。
Purpose: Experimental partial bladder outlet obstruction of rats induces a bladder growth and remodeling process similar to that in humans with benign prostatic hyperplasia. Previously we have proposed that bladder hypoxia associated with partial bladder outlet obstruction is a stimulus of this bladder growth process. We report our results of testing the acute effects of a simple chemical agent (cobaltous ion) known to mimic hypoxia in the rat bladder. We measured its ability to effect bladder gene expression, angiogenesis and growth processes.Materials and Methods: Adult rats were divided into 2 groups. One group (controls) received intravesical saline 3 times for 30 minutes in 6 days and the other received intravesical saline with 100 muM. CoCl2 at the same times. All animals also received continuous infusion of BrdU for the 6-day period through an implanted osmotic pump. Portions of the bladders from these rats were fixed, sectioned, stained for microscopic analysis and immunohistochemically stained to identify BrdU positive cells and vascular elements via factor VIII staining. Other portions were frozen, extracted for proteins and the proteins were comparatively analyzed for the expression of hypoxia inducible factor-1alpha and vascular endothelial growth factor on Western blots.Results: Bladders infused with CoCl2 showed extensive expansion of the submucosal region, which was significant compared with that in saline infused bladders. Cells in this expanded region as well as cells within the urothelium were found to be extensively labeled with BrdU, in contrast to control bladders, which had rare BrdU labeled cells in any region. Immunohistochemical analysis for factor VIII showed that the submucosal region of cobalt treated rats contained numerous small vessels and microvessels that were not apparent in controls. These cellular changes were consistent with our finding of increased hypoxia inducible factor-1alpha and vascular endothelial growth factor protein expression in cobalt treated bladders compared with controls.Conclusions: Acute intravesical instillation of cobalt ion solution into the rat bladder initiated hypoxia response accompanied by increased bladder angiogenesis and growth. This finding supports the idea that hypoxia is a stimulus for bladder growth subsequent to partial bladder outlet obstruction.