Fluid Forces Control Structural Remodeling of Blind-Ended Lymphatic Microvessels

The transport function of lymphatic vessels is altered during tissue injury, inflammation, and cancer. Defects in lymphatic function are associated with changes to the biophysical microenvironment, including pressure and flow. However, the ability of fluid forces to orchestrate the remodeling of blind-ended lymphatic vessels and lymphangiogenesis is not well understood. Here, a novel microphysiological system (MPS) is developed that recapitulates the blind-ended microanatomy and fluid absorption properties of capillary lymphatics. This MPS implements a continuum of pressure-driven interstitial, transmural, and luminal flow to mimic fluid forces naturally present within the lymphatic microenvironment. Interstitial flow (IF) and vascular endothelial growth factor C (VEGF-C) cooperated during lymphangiogenesis. Notably, sprouting was most prominent at the blind-ended region of lymphatic vessels where transmural flow was highest in the MPS. Moreover, IF guided invading sprouts into the surrounding extracellular matrix (ECM) antiparallel to streamlines within a nonuniform three-dimensional (3-D) flow field. Strikingly, flow-induced elongation and axial alignment of intraluminal cells propagated to vessel-level phenotypic differences, such as vasoconstriction and helical patterning. The structural remodeling of these lymphatic vessels was concurrent with lymphangiogenesis. These results reveal how extravascular and intraluminal endothelial cells integrate signals from native fluid forces to coordinate the expansion and remodeling of capillary lymphatics.