Mechanisms of lymphatic valve and pump dysfunction in lymphedema

淋巴水肿中淋巴瓣和淋巴泵功能障碍的机制

• 批准号: 8898205
• 负责人: Michael John Davis
• 金额: $ 36.36万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898205
• 关键词: Adrenergic Agonists; Affect; Caliber; Clinical Research; Compression Stocking; Development; Diastolic blood pressure; Edema; Environment; Exhibits; Failure; Functional disorder; Health; Hydrostatic Pressure; In Vitro; Knockout Mice; Knowledge; Laboratories; Lead; Left; Limb structure; Lymph; Lymphatic; Lymphatic Diseases; Lymphatic System; Lymphatic vessel; Lymphedema; Maintenance; Massage; Measures; Mechanics; Methods; Modeling; Mus; Muscle; Output; Permeability; Phenotype; Positioning Attribute; Property; Prophylactic treatment; Protocols documentation; Pump; Secondary to; Series; System; Systole; Testing; design; efficacy testing; experience; human disease; in vivo; insight; lymphatic pump; mouse model; novel; palliative; premature; pressure; prevent; primary lymphedema; response; transcription factor

DESCRIPTION (provided by applicant): Lymph transport occurs against a hydrostatic pressure gradient and thus relies critically on the intrinsic contractile function of lymphatic muscle, the "lymphatic pump". Failure of this pump system is associated with many forms of lymphedema, afflicting over 10 million people annually in the USA. Little is known about how and why lymphatic vessels become dysfunctional in lymphedema. Clinical studies reveal that lymphatic diastolic pressure is elevated, vessel diameter enlarged, contraction amplitude severely impaired, and the valves apparently incompetent. Yet these findings are post-hoc and do not provide insight into cause or effect. We have recently pioneered methods for quantitative studies of lymphatic valve and pump function in isolated single lymphangions and chains of lymphangions in the mouse; thus we can rigorously test pump function when a lymphangion is subjected under defined conditions to increased pressure loads where all pressures, diameters and valve positions are known or controlled. Additionally, we can do this in mouse models of lymphatic disease. Our results reveal that two types of pump failure occur, even in healthy vessels, in response to a progressive rise in inflow / outflow pressure, simulating the pressure load on the vessel in a dependent extremity. 1) The pump either gradually weakens until it cannot eject, leaving the output valve closed; or 2) the output valve "locks" open, with catastrophic consequences, as pressure across it equilibrates in systole. Valve lock is exacerbated in mice deficient in the transcription factor FOXC2, which controls the development and maintenance of lymphatic valves; its deficiency recapitulates the human disease lymphedema distichiasis. Importantly, both conditions can be corrected. We will test the mechanisms leading to contractile and valve dysfunction in the hydrostatic environment experienced by the lymph pump during the development of lymphedema, utilizing both healthy and Foxc2-deficient mice Single or multiple lymphangions will be isolated from murine popliteal and inguinal lymphatic networks and studied in vitro; we will then apply the concepts to the study of inguinal lymphatic networks in vivo. Our central hypothesis is that the efficiency of the lymphatic pump under an imposed load depends on the interaction of three key variables: the mechanical properties of lymphatic muscle, the properties of the valves, and the coordination of the contraction wave; further, we propose that pump dysfunction can be reversed by α-adrenergic agonists. Aims: 1) Determine the mechanisms underlying valve lock and pump failure when healthy lymphangions are forced to pump against elevated outflow pressure; 2) Determine the consequences of lymphatic valve and pump dysfunction in Foxc2+/- and inducible Foxc2-/- models of primary lymphedema; 3) Determine the principles by which lymph pump dysfunction can be rescued pharmacologically in healthy and Foxc2-deficient vessels. This approach to treating a failed lymph pump represents a potential new strategy for treating a common underlying contributor to many forms of both congenital and acquired lymphedema.

描述（由适用提供）：淋巴运输是针对静水压力梯度发生的，因此非常依赖淋巴肌肉的内在收缩功能，即“淋巴泵”。该泵系统的故障与多种形式的淋巴Dema有关，每年在美国遭受超过1000万人的折磨。关于淋巴vissel在淋巴DEMA中的功能失调的知之甚少。临床研究表明，淋巴舒张压升高，血管直径扩大，合同放大器严重受损，瓣膜显然无能。然而，这些发现是事后的，并且没有提供有关原因或影响的见解。我们最近在小鼠中孤立的单个淋巴管和淋巴机的淋巴管和泵功能的定量研究中进行了策划方法。因此，当淋巴管在定义的条件下进行淋巴管时，我们可以严格测试泵的功能，以增加所有压力，直径和阀位置的压力负荷。此外，我们可以在淋巴病小鼠模型中这样做。我们的结果表明，即使在健康的vissels中，也会发生两种类型的泵衰竭，以响应流入 /出口压力的逐步上升，从而模拟了依赖性极端的容器上的压力负载。 1）泵要么逐渐削弱，直到无法弹出，使输出阀关闭；或2）输出阀“锁”打开，带有灾难性后果，因为横跨其的压力在收缩期中平衡。在转录因子FOXC2缺乏的小鼠中，瓣膜锁会加剧，该小鼠控制淋巴瓣的发育和维护；它的缺乏概括了人类疾病淋巴水肿的疾病。重要的是，可以纠正这两种情况。我们将测试导致淋巴水肿在淋巴水肿过程中经历的静液压环境中导致收缩和瓣膜功能障碍的机制，利用健康和FOXC2缺陷小鼠单一或多个淋巴管将从鼠类流行和inguine淋巴网络和辅助淋巴网络和研究中分离出一种或多个淋巴管。然后，我们将将这些概念应用于体内腹股沟淋巴网络的研究。我们的中心假设是，在施加的负载下，淋巴泵的效率取决于三个关键变量的相互作用：淋巴肌肉的机械性能，瓣膜的特性和收缩波的配位；此外，我们建议泵功能障碍可以被α-肾上腺素能激动剂逆转。目的：1）确定阀门锁定和泵衰竭的机制，当时健康的淋巴肌肉被迫在出口压力上泵送； 2）确定FOXC2 +/-和诱导型FOXC2 - / - 原发性淋巴水肿模型中淋巴瓣和泵功能障碍的后果； 3）确定可以在健康和FOXC2缺乏容器中物理救出淋巴泵功能障碍的原理。这种治疗失败淋巴泵的方法代表了一种潜在的新策略，用于治疗多种形式的先天性淋巴水肿的常见基础贡献者。