Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
BJU Int. 2010 Nov;106(9):1394-9. doi: 10.1111/j.1464-410X.2010.09237.x.
To 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.
Bladders 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 mm(2) pieces and cultured overnight. Culture media were collected 24 h later for VEGF assay. C57BL/6 bladder was processed for CRH-R immunohistochemistry.
Acute 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.
Acute 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.
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会加重某些炎症性疾病，包括间质性膀胱炎/疼痛性膀胱综合征（IC / PBlS），其特征是疼痛、膀胱炎症的变化、膀胱血管内皮生长因子（VEGF）的表达增加以及许多逼尿肌肥大细胞。
在麻醉下对正常 C57BL/6 和源自 C57BL/6 的 CRH-R1、CRH-R2 或双重 CRH-R1 + 2 敲除（-/-）雌性小鼠（10-12 周龄）的膀胱进行导管插入术。排空尿液后，用生理盐水对 C57BL/6 小鼠进行灌洗，然后在束缚器中放置 30 分钟以施加压力。在施加压力前，尾静脉注射 Evans 蓝以进行通透性实验。然后取出 C57BL/6 或 CRH-R -/- 小鼠的膀胱，切成 1mm2 小块并培养过夜。24 小时后收集培养基以进行 VEGF 测定。处理 C57BL/6 膀胱以进行 CRH-R 免疫组织化学。
急性应激增加了对照 C57BL/6 和 CRH-R1 -/- 小鼠的膀胱血管通透性，但不会增加 CRH-R2 -/- 或 CRH-R1 + 2 -/- 小鼠的膀胱血管通透性。CRH-R2 拮抗剂 Astressin 2B，但不是 CRH-R1 拮抗剂 Antalarmin，可抑制应激诱导的 C57BL/6 小鼠膀胱外植体中 VEGF 的释放。应激不能诱导 CRH-R2 -/- 或 CRH-R1 + 2 -/- 小鼠的膀胱外植体中 VEGF 的增加，但可以诱导 CRH-R1 -/- 小鼠的膀胱外植体中 VEGF 的增加。在 C57BL/6 膀胱中检测到膀胱 CRH-R2 免疫反应性。
急性应激诱导的膀胱血管通透性和 VEGF 释放依赖于 CRH-R2。这些发现表明 CRH 和 VEGF 可能参与 IC / PBlS 的发病机制，并为新的治疗靶点提供了依据。
