Lymphatic vessel mechanics: a clue towards treating lymphedema

Abstract

Lymphedema, a debilitating disease characterized by a disfiguring swelling of the extremities, affects nearly 140 to 250 million people worldwide. In the US the primary cause of lymphedema is breast cancer related surgery and it can affect about 70% of the patients depending on the nature of the surgery and any secondary insult. The exact pathogenesis of lymphedema is not clear and diagnosis usually happens at a late stage. Further, the treatment of lymphedema is rarely corrective and focuses more on disease management. One of the primary causes of lymphedema is suspected to be dysfunctions in the lymphatic system. The lymphatic system is a complex network of vessels and nodes that plays an important role in the maintenance of the tissue fluid balance in the body. Lymphatic vessels have been shown to modulate their contractility in response to mechanical forces like transmural pressure and flow induced shear stress (referred to as shear sensitivity). Reduction in shear sensitivity of the lymphangions is suspected to be a major cause of lymphatic dysfunction and, in turn, lymphedema. Hence, it is important to understand how the shear sensitivity of the lymphatic vessel affects the contractility of the vessel in response to the dynamic mechanical microenvironment within the lymphatic vessels. The molecular mechanisms involved in the shear sensitivity of lymphangions also need to be delineated. Finally it is important to investigate whether the lymphatic vessel function can be optimized through mechanical stimulation. These central questions will be approached from three different length scales; in vitro through molecular mechanisms of mechanosensitivity, ex vivo through functional response of lymphatic vessels to oscillatory shear stress and in vivo through reduction in swelling in animals using external oscillatory mechanical stimuli. These aims will lead to the identification of some of the molecular pathways involved in the transduction of shear stress by lymphatic endothelial cells and will motivate studies into pharmacological modulation of lymphatic contractility to maximize its response to oscillatory shear stresses. Quantifying the effect of externally applied pressure, such as those applied during physiotherapy, will provide a scientific basis for enhancing lymphatic system function noninvasively.