Fluid Forces Control Structural Remodeling of Blind-Ended Lymphatic Microvessels

Area of Science:

• Biomedical Engineering
• Cell Biology
• Physiology

Background:

• Lymphatic vessel function is critical for tissue homeostasis and is impaired in diseases like cancer.
• Biophysical factors such as pressure and flow within the lymphatic microenvironment are altered during disease.
• The role of fluid forces in guiding lymphatic vessel remodeling and lymphangiogenesis remains poorly understood.

Purpose of the Study:

• To investigate how fluid forces orchestrate the remodeling of blind-ended lymphatic vessels.
• To explore the mechanisms of lymphangiogenesis driven by microenvironmental fluid dynamics.
• To develop a novel microphysiological system (MPS) that mimics capillary lymphatic anatomy and function.

Main Methods:

• Development of a novel microphysiological system (MPS) to simulate interstitial, transmural, and luminal flow.
• Utilizing the MPS to study the interplay between interstitial flow (IF) and vascular endothelial growth factor C (VEGF-C) in lymphangiogenesis.
• Analyzing the effects of fluid forces on lymphatic vessel sprouting, cell alignment, and structural remodeling.

Main Results:

• Interstitial flow (IF) and VEGF-C synergistically promoted lymphangiogenesis.
• Lymphatic sprouting was most pronounced in regions of high transmural flow at the blind ends of vessels.
• Fluid forces induced cell alignment and vessel-level phenotypic changes, including vasoconstriction and helical patterning.
• Structural remodeling and lymphangiogenesis occurred concurrently, coordinated by endothelial cells responding to fluid forces.

Conclusions:

• Extravascular and intraluminal endothelial cells integrate signals from native fluid forces to coordinate lymphatic vessel expansion and remodeling.
• The developed MPS effectively recapitulates key aspects of capillary lymphatic function and response to fluid dynamics.
• Understanding these flow-mediated mechanisms is crucial for addressing lymphatic dysfunction in disease.