Interstitial Flow as a Guide for Lymphangiogenesis

Abstract

Abstract-The lymphatic system is important in tissue fluid balance regulation, immune cell trafficking, edema, and cancer metastasis, yet very little is known about the sequence of events that initiate and coordinate lymphangiogenesis. Here, we characterize the process of lymphatic regeneration by uniquely correlating interstitial fluid flow and lymphatic endothelial cell migration with lymphatic function. A new model of skin regeneration using a collagen implant in a mouse tail has been developed, and it shows that (1) interstitial fluid channels form before lymphatic endothelial cell organization and (2) lymphatic cell migration, vascular endothelial growth factor-C expression, and lymphatic capillary network organization are initiated primarily in the direction of lymph flow. These data suggest that interstitial fluid channeling precedes and may even direct lymphangiogenesis (in contrast to blood angiogenesis, in which fluid flow proceeds only after the vessel develops); thus, a novel and robust model is introduced for correlating molecular events with functionality in lymphangiogenesis.

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

“…This would result in tumour cells having a greater likelihood of detecting lymphatic-secreted chemokines to identify the lymphatics (Podgrabinska et al, 2002), and being able to secrete heparin-binding growth factors a further distance to stimulate lymphatic growth into the tumours. Recent studies have also shown that lymphatic cells can migrate along patterns of interstitial fluid flows (Boardman and Swartz, 2003), and presumably this would be enhanced in more permeable tumours. Thus, the expression characteristics of these tumours indicate that upregulation of pro-angiogenic, pro-permeability VEGF 165 and its sister isoforms is associated with metastasis in melanoma.…”

Expansion of Cortical and Medullary Sinuses Restrains Lymph Node Hypertrophy during Prolonged Inflammation

“…Interstitial flow acting in concert with lymphangiogenic factors was reported to be a key driving force of lymphangiogenesis (41,42). Moreover, alterations in interstitial flow were shown to affect the expression of chemokines by FRCs (43).…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…In addition to regulating function, fluid flow is also an important regulator of lymphatic morphogenesis or lymphangiogenesis, and has been shown to drive lymphatic capillary organization in dermal wound healing models [45,46] as well as in vitro culture models [47][48][49]. Without flow, as in the case of lymphedema, lymphatic endothelium becomes hyperplastic (i.e.…”