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 ?- 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.

Public Health Relevance

Lymphedema affects over 10 million people annually in the USA, yet surprisingly little is known about how and why lymphatic vessels become dysfunctional in lymphedema. Current therapies are limited to palliative measures (massage, compression stockings) that do not treat the major underlying cause, which is failure of the intrinsic lymphati vessel pump. In this project we will study the lymphatic vessel pump in healthy mice after subjection to high pressure loads that are experienced in acquired lymphedema. These responses will be compared to vessels from a knock-out mouse model of congenital lymphedema, in which valves in the lymphatic system are missing or improperly formed, recapitulating the human disease lymphedema distichiasis. We will test the efficacy of novel pharmacological approaches to treating both healthy and defective lymphatic vessels. Rescue of the failed lymph pump could represent a potential new strategy for treating a common underlying cause of lymphedema.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Tolunay, Eser
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University of Missouri-Columbia
Schools of Medicine
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Zawieja, Scott D; Castorena-Gonzalez, Jorge A; Scallan, Joshua P et al. (2018) Differences in L-type Ca2+ channel activity partially underlie the regional dichotomy in pumping behavior by murine peripheral and visceral lymphatic vessels. Am J Physiol Heart Circ Physiol 314:H991-H1010
Bertram, C D; Macaskill, C; Davis, M J et al. (2018) Contraction of collecting lymphatics: organization of pressure-dependent rate for multiple lymphangions. Biomech Model Mechanobiol 17:1513-1532
Zawieja, Scott D; Castorena-Gonzalez, Jorge A; Dixon, Brandon et al. (2017) Experimental Models Used to Assess Lymphatic Contractile Function. Lymphat Res Biol 15:331-342
Jamalian, Samira; Jafarnejad, Mohammad; Zawieja, Scott D et al. (2017) Demonstration and Analysis of the Suction Effect for Pumping Lymph from Tissue Beds at Subatmospheric Pressure. Sci Rep 7:12080
Lapinski, Philip E; Lubeck, Beth A; Chen, Di et al. (2017) RASA1 regulates the function of lymphatic vessel valves in mice. J Clin Invest 127:2569-2585
Munger, Stephanie J; Davis, Michael J; Simon, Alexander M (2017) Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43. Dev Biol 421:204-218
Bertram, C D; Macaskill, C; Davis, M J et al. (2017) Valve-related modes of pump failure in collecting lymphatics: numerical and experimental investigation. Biomech Model Mechanobiol 16:1987-2003
Behringer, Erik J; Scallan, Joshua P; Jafarnejad, Mohammad et al. (2017) Calcium and electrical dynamics in lymphatic endothelium. J Physiol 595:7347-7368
Ivanov, Stoyan; Scallan, Joshua P; Kim, Ki-Wook et al. (2016) CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability. J Clin Invest 126:1581-91
Bertram, Christopher D; Macaskill, Charlie; Davis, Michael J et al. (2016) Consequences of intravascular lymphatic valve properties: a study of contraction timing in a multi-lymphangion model. Am J Physiol Heart Circ Physiol 310:H847-60

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