Regulation of pelvic pain and micturition reflex by VEGF in urological chronic pelvic pain syndrome

项目总结 泌尿系慢性盆腔疼痛综合征(UCPPS)是一种复杂的、多因素的疾病 由排尿和/或性功能障碍、内脏痛觉过敏和慢性盆腔疼痛(CPP)引起。以前的动物 我们实验室的研究证实，外周神经源性炎症与中枢 致敏作用在UCPPS症状的产生和维持中起作用。来自Mapp的最新研究 网络证实，血管内皮生长因子可能是尿路感染的潜在生物标志物之一。具体来说，患者 UCCPS患者尿中血管内皮生长因子及其受体水平明显高于正常对照组。 此外，疼痛的严重程度与尿液中血管内皮生长因子的升高显著相关，这表明它可能起作用。 作为UCPPS的临床有用的诊断标记物。尽管有这种新的临床数据，但其部位和机制 血管内皮生长因子在控制排尿的中枢神经系统中的作用及其对周围和中枢神经元兴奋性的影响 下尿路(LUT)的神经支配尚不清楚。因此，机械介入的论证 研究血管内皮生长因子在膀胱疼痛和排尿功能障碍中的作用将提供科学依据和“概念验证”数据 用于设计抗血管内皮生长因子治疗以减轻UCPPS患者下尿路综合征和膀胱疼痛的临床试验。虽然这个角色 血管内皮生长因子在血管生成中的作用已经得到了很好的证实，但对其参与血管生成的了解则更少。 内脏痛的神经发生。我们是第一个提供直接证据证明膀胱内灌输 小鼠体内的血管内皮生长因子促进了感觉神经和运动神经密度的显著增加，这与 有尿流动力学记录的逼尿肌过度活动和腹部敏感度增强。当前应用程序 建立在我们最初发现的基础上，并专注于确定血管内皮生长因子调节神经的机制 支配下尿路的膀胱周围神经元和脊髓神经元的可塑性。它还将探索潜在的 血管内皮生长因子激活的膀胱伤害性(疼痛相关)通路与排尿反射的交叉效应 正如在UCPPS患者中观察到的那样。其他研究将测试药理学方法，使用现有的 应用血管内皮细胞生长因子中和抗体评价其限制痛觉和恢复膀胱功能的潜力 膀胱疼痛和排尿功能障碍的翻译动物模型。总体而言，这项研究将产生新颖的、 可解释的数据，以假设驱动的补充方式扩展最近的Mapp研究，并将填补 为慢性病患者开发个体化治疗方法所需的知识差距 UCPPS。

PROJECT SUMMARY Urological Chronic Pelvic Pain Syndrome (UCPPS) is a complex and multifactorial disorder characterized by voiding and/or sexual dysfunction, visceral hyperalgesia, and chronic pelvic pain (CPP). Previous animal studies from our laboratory established that peripheral neurogenic inflammation together with central sensitization play a role in generation and maintenance of UCPPS symptoms. Recent study from the MAPP network confirmed that VEGF could be one of the potential urinary biomarkers of UCPPS. Specifically, patients with UCCPS had significantly higher levels of urinary VEGF and VEGF receptors than healthy controls. Additionally, pain severity was significantly associated with increased urinary VEGF suggesting that it may serve as a clinically useful diagnostic marker for UCPPS. Despite this novel clinical data, the sites and mechanisms of VEGF action in the CNS centers controlling micturition, effects on excitability of peripheral and central neurons innervating the lower urinary tract (LUT) are still unknown. Therefore, demonstration of mechanistic involvement of VEGF in bladder pain and voiding dysfunction would provide scientific justification and “proof-of-concept” data for designing clinical trials of anti-VEGF treatments to alleviate LUTS and bladder pain in UCPPS. While the role of VEGF in angiogenesis has been previously well established, much less is known about its participation in neurogenesis of visceral pain. We were the first group to provide direct evidence that intravesical instillation of VEGF in mice promoted a significant increase in density of both sensory and motor nerves, which was associated with urodynamically recorded detrusor overactivity and enhanced abdominal sensitivity. Current application builds upon our initial findings, and is focused on determining the mechanisms by which VEGF modulates neural plasticity of bladder peripheral and spinal neurons innervating the lower urinary tract. It will also explore potential cross-effects of the VEGF-activated bladder nociceptive (pain-associated) pathways with the micturition reflex, as observed in patients with UCPPS. Additional studies will test pharmacological approaches using available VEGF neutralizing antibodies to evaluate their potential to limit pain sensation and restore bladder function using translational animal models of bladder pain and voiding dysfunction. Overall, the study will result in novel, interpretable data that expands recent MAPP studies in a hypothesis-driven complementary fashion, and will fill the knowledge gap necessary for the development of individualized therapeutic approaches for patients with UCPPS.