Cellular and Molecular Immunology · 2 authors, 2 centres
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This review summarizes how lymphatic vessels sense and respond to fluid shear stress and other mechanical forces, which regulate their structure, permeability, and immune functions. Key mechanosensors include the PECAM/VE-cadherin/VEGFR2/VEGFR3 complex and Piezo1, which activate downstream pathways controlling lymphatic development and remodeling. Understanding these biomechanical controls may lead to new therapies for lymphedema and other diseases involving lymphatic dysfunction.
**Background:** The lymphatic system, once considered a secondary vascular network, is now recognized as vital for tissue homeostasis, immune surveillance, and lipid transport. Lymphatic dysfunction is linked to lymphedema, inflammatory bowel disease, obesity, cardiovascular disease, and neurological disorders. While biochemical signals like VEGF-C are known regulators, emerging evidence shows that mechanical forces—particularly fluid shear stress (FSS)—also shape lymphatic vessel phenotype and function. This review focuses on how lymphatic endothelial cells (LECs) sense and transduce FSS, and how these biomechanical signals influence lymphatic physiology and pathology.
**Methods:** This is a narrative review that synthesizes findings from in vitro studies (e.g., LEC cultures under laminar or oscillatory shear stress), in vivo animal models (e.g., mice with genetic deletions of Piezo1, ORAI1, FOXC2, or PROX1), and human case reports. The authors describe mechanosensory complexes and signaling pathways identified through molecular, cellular, and genetic approaches.
**Key Results:** LECs are exposed to FSS ranging from 0–12 dynes/cm² in rat mesenteric lymphatics up to 40 dynes/cm² in lymphedema models. Laminar shear stress (LSS) at 4 dynes/cm² induces LEC elongation and alignment with flow, while oscillatory shear stress (OSS) at 4 dynes/cm² and ¼ Hz produces cuboidal cells resembling lymphatic valve cells. The FSS set point for LECs is 4–10 dynes/cm², lower than blood endothelial cells (10–20 dynes/cm²), due to higher VEGFR3 expression. FSS activates VEGFR3 phosphorylation via β1 integrin and the PI3K/Akt pathway. Two mechanosensing mechanisms are identified: (1) a complex of PECAM, VE-cadherin, VEGFR2, and VEGFR3 at cell junctions, and (2) the ion channel Piezo1, which activates ORAI1-mediated calcium entry. Downstream, calcium-calmodulin complexes with KLF2, upregulating VEGF-C, VEGF-A, and FGFR3 while downregulating p57. OSS upregulates FOXC2 and PROX1, which induce Cx37 and NFATc1, and FOXC2-deficient LECs show disrupted junctions and hyperproliferation via YAP/TAZ. In vivo, Piezo1 deletion reduces mesenteric and dermal lymphatics, while its agonist Yoda-1 promotes lymphangiogenesis and improves lymphedema in mice. FSS also enhances lymphatic permeability, CCL21 expression, and dendritic cell migration. Synergy between FSS and VEGF-C or S1P modulates sprouting and remodeling.
**Clinical Implications:** Understanding mechanotransduction in lymphatics opens new therapeutic avenues. Targeting Piezo1 with agonists like Yoda-1 shows preclinical promise for treating secondary or primary lymphedema by promoting functional lymphatic vessel growth. Restoring optimal lymphatic function may also benefit diseases involving lipid accumulation (e.g., atherosclerosis, obesity), immune dysfunction (e.g., inflammatory bowel disease), and neurological disorders (e.g., Alzheimer's). However, challenges remain in distinguishing biomechanical from biochemical signals, as many downstream molecules overlap. Future research should develop tools to visualize lymph flow and study how multiple mechanical cues are integrated in pathological settings.