Corticotropin-releasing hormone-receptor 2 is required for acute stress-induced bladder vascular permeability and release of vascular endothelial growth factor
Corticotropin-releasing hormone-receptor 2 is required for acute stress-induced bladder vascular permeability and release of vascular endothelial growth factor
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DOI：
10.1111/j.1464-410x.2010.09237.x
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发表时间：
2010-11-01
影响因子：
4.5
通讯作者：
Theoharides, Theoharis C.
中科院分区：
文献类型：
--
作者：
Boucher, William;Kempuraj, Duraisamy;Theoharides, Theoharis C.
目的研究促肾上腺皮质激素释放激素（CRH）受体（CRH-R）在急性应激对膀胱血管通透性和血管内皮生长因子（VEGF）释放的影响中的作用，因为越来越多的证据表明急性应激可引起某些炎症性疾病，包括间质性膀胱炎/膀胱疼痛综合征（IC/PBIS），其特征在于疼痛、可变性膀胱炎症、膀胱血管内皮生长因子（VEGF）和许多逼尿肌肥大细胞的表达增加。材料和方法将正常C57 BL/6和C57 BL/6衍生的CRH-R1、CRH-R2或双CRH-R1 + 2敲除（-/-）雌性小鼠（10-12周龄）的膀胱在麻醉下插入导管。C57 BL/6小鼠在排空尿液后，分别用生理盐水和CRH-R拮抗剂进行膀胱灌注，然后将其置于束缚器中30 min。在应激前尾静脉注射Evans蓝进行通透性实验。然后取出来自C57 BL/6或CRH-R -/-小鼠的膀胱，切碎成1 mm 2的片并培养过夜。24小时后收集培养基用于VEGF测定。C57 BL/6膀胱进行CRH-R免疫组织化学处理。C57 BL/6和CRH-R1 -/-小鼠膀胱血管通透性增加，而CRH-R2 -/-或CRH-R1+2 -/-小鼠膀胱血管通透性增加。CRH-R2拮抗剂Astressin 2B（而不是CRH-R1拮抗剂Antalarmin）抑制C57 BL/6小鼠膀胱外植体中应激诱导的VEGF释放。应激不能诱导CRH-R2 -/-或CRH-R1+2 -/-小鼠膀胱外植体的VEGF增加，但在CRH-R1 -/-小鼠中可以诱导VEGF增加。膀胱CRH-R2免疫反应性检测C57 BL/6 bladders.CONCLUSIONSAcute应激诱导膀胱血管通透性和VEGF的释放是依赖于CRH-R2。这些结果提示CRH和VEGF可能参与IC/PBLS的发病机制，并为IC/PBLS的治疗提供了新的靶点。
OBJECTIVETo investigate the corticotropin-releasing hormone (CRH) receptor (CRH-R) requirement for the effect of acute stress on bladder vascular permeability and release of vascular endothelial growth factor (VEGF), as increasing evidence indicates that acute stress worsens certain inflammatory disorders, including interstitial cystitis/painful bladder syndrome (IC/PBlS), which is characterized by pain, variable bladder inflammation, increased expression of bladder vascular endothelial growth factor (VEGF), and many detrusor mast cells.MATERIALS AND METHODSBladders of normal C57BL/6, and C57BL/6- derived CRH-R1, CRH-R2 or double CRH-R1 + 2 knockout (-/-) female mice (10-12 weeks old) were catheterized under anaesthesia. After emptying the urine, normal saline was instilled with or without intravesical CRH-R antagonists in C57BL/6 mice before they were stressed by placing them in a restrainer for 30 min. Evans blue was injected in the tail vein before stress for the permeability experiments. The bladders from C57BL/6 or CRH-R -/- mice were then removed, minced into 1 mm2 pieces and cultured overnight. Culture media were collected 24 h later for VEGF assay. C57BL/6 bladder was processed for CRH-R immunohistochemistry.RESULTSAcute stress increased bladder vascular permeability in control C57BL/6 and CRH-R1 -/- mice, but not CRH-R2 -/- or CRH-R1+2 -/- mice. The CRH-R2 antagonist Astressin 2B, but not the CRH-R1 antagonist Antalarmin, inhibited stress-induced VEGF release from C57BL/6 mouse bladder explants. Stress could not induce a VEGF increase from bladder explants of CRH-R2 -/- or CRH-R1+2 -/- mice, but did so in CRH-R1 -/- mice. Bladder CRH-R2 immunoreactivity was detected in C57BL/6 bladders.CONCLUSIONSAcute stress induces bladder vascular permeability and VEGF release that is dependent on CRH-R2. These findings suggest that CRH and VEGF might participate in the pathogenesis of IC/PBlS and provide for new therapeutic targets.