Wenjin Zhang
BME MS Thesis Defense Presentation
Date: 2026-04-17
Time: 10:30 - 12:00 pm
Location / Meeting Link: IBB 1316

Committee Members:
Dr. Brandon Dixon (Advisor), Dr. Shuichi Takayama, Dr. Susan Thomas


Title: MECHANICAL DYSFUNCTION IN LYMPHATIC MALFORMATION ENDOTHELIAL CELLS UNDER WALL SHEAR STRESS

Abstract:
Lymphatic malformations (LMs) are rare congenital vascular anomalies driven by somatic PIK3CA mutations that cause constitutive PI3K/AKT hyperactivation and uncontrolled lymphatic endothelial cell (LEC) proliferation. While the genetic basis of LM is increasingly understood, the role of biomechanical factors in disease progression remains poorly characterized. Healthy LECs continuously sense fluid shear stress generated by lymph flow, and proper mechanosensing is essential for vascular quiescence. Thus we want to answer the question of how LM cells respond to shear stress and how this mechanical clue contributes to disease progression. We first hypothesized that LM derived cells exhibit impaired mechanotransduction compared to healthy human dermal lymphatic endothelial cells (HDLECs) under wall shear stress. Patient-derived LM cells with PIK3CA mutations and HDLECs were subjected to controlled steady laminar wall shear stress using an in vitro microfluidic flow system. Cytoskeletal responses were quantified by actin fiber orientation, alignment index, and deviation angle relative to flow direction. Experimental result showed that LM-derived cells failed to align in response to shear stress while HDLECs align in the flow direction. To investigate whether this failure stems from a breakdown of mechanosensory pathways, we inhibited VEGFR3 in healthy HDLECs. This recapitulated the LM phenotype, demonstrating that VEGFR3 is required for flow sensing. Further immunofluorescence analysis showed that VE-cadherin junctional protein was either absent or mislocalized in LM cells, indicating structural collapse of the endothelial mechanosensory complex that can lead to mechanical dysfunction. This work highlights the critical role of mechanical dysfunction in LMs and provides insights on how disrupted mechanosensing can contribute to LM disease progression.