Goldman Jeremy, Conley Kelly A, Raehl Alisha, Bondy Dona M, Pytowski Bronislaw, Swartz Melody A, Rutkowski Joseph M, Jaroch David B, Ongstad Emily L
Biomedical Engineering Department, Michigan Technological University, Houghton, MI 49931, USA.
Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2176-83. doi: 10.1152/ajpheart.01011.2006. Epub 2006 Dec 22.
Decreased interstitial flow (IF) in secondary lymphedema is coincident with poor physiological lymphatic regeneration. However, both the existence and direction of causality between IF and lymphangiogenesis remain unclear. This is primarily because the role of IF and its importance relative to the action of the prolymphangiogenic growth factor vascular endothelial growth factor (VEGF)-C (which signals primarily through its receptor VEGFR-3) are poorly understood. To clarify this, we explored the cooperative roles of VEGFR-3 and IF in a mouse model of lymphangiogenesis in regenerating skin. Specifically, a region of lymphangiogenesis was created by substituting a portion of mouse tail skin with a collagen gel within which lymphatic capillaries completely regenerate over a period of 60 days. The relative importance of IF and VEGF-C signaling were evaluated by either inhibiting VEGFR-3 signaling with antagonistic antibodies or by reducing IF. In some cases, VEGF-C signaling was then increased with exogenous protein. To clarify the role of IF, the distribution of endogenous matrix metalloproteinases (MMPs) and VEGF-C within the regenerating region was determined. It was found that inhibition of either VEGFR-3 or IF suppressed endogenous lymphangiogenesis. Reduction of IF was found to decrease lymphatic migration and transport of endogenous MMP and VEGF-C through the regenerating region. Therapeutic VEGF-C administration restored lymphangiogenesis following inhibition of VEGFR-3 but did not increase lymphangiogenesis following inhibition of IF. These results identify IF as an important regulator of the pro-lymphangiogenic action of VEGF-C.
继发性淋巴水肿中间质流（IF）减少与生理性淋巴管再生不良同时出现。然而，IF与淋巴管生成之间因果关系的存在及方向仍不明确。这主要是因为IF的作用及其相对于促淋巴管生成生长因子血管内皮生长因子（VEGF）-C（主要通过其受体VEGFR-3发出信号）作用的重要性尚未得到充分理解。为了阐明这一点，我们在再生皮肤淋巴管生成的小鼠模型中探究了VEGFR-3和IF的协同作用。具体而言，通过用胶原凝胶替代小鼠尾部皮肤的一部分来创建一个淋巴管生成区域，在该区域内淋巴管在60天内完全再生。通过用拮抗抗体抑制VEGFR-3信号或减少IF来评估IF和VEGF-C信号的相对重要性。在某些情况下，然后用外源性蛋白增加VEGF-C信号。为了阐明IF的作用，确定了内源性基质金属蛋白酶（MMPs）和VEGF-C在再生区域内的分布。发现抑制VEGFR-3或IF均会抑制内源性淋巴管生成。发现减少IF会减少内源性MMP和VEGF-C通过再生区域的淋巴迁移和运输。抑制VEGFR-3后给予治疗性VEGF-C可恢复淋巴管生成，但抑制IF后不会增加淋巴管生成。这些结果确定IF是VEGF-C促淋巴管生成作用的重要调节因子。
