Date of Award
2024
Document Type
Campus Access Dissertation
Degree Name
Doctor of Philosophy in Biomedical Engineering (PhD)
Administrative Home Department
Department of Biomedical Engineering
Advisor 1
Sangyoon J Han
Committee Member 1
Smitha Rao Hatti
Committee Member 2
Hoda Hatoum
Committee Member 3
Mark Tang
Abstract
Hemodynamic forces in blood vessels regulate vascular remodeling, homeostasis, and disease progression. Among these forces, fluid shear stress (FSS) is sensed by endothelial cells (ECs), which elicit signals regulating vascular health. ECs experience variations in FSS based on their location within the vasculature, such as aorta, arteries, veins, bifurcations, constrictions, curves, or expansions. High, laminar FSS promotes atheroprotective gene expression, whereas low or oscillatory FSS induces dysfunction and inflammation. However, the adaptation of ECs to dynamically changing FSS patterns remains underexplored.
We combined traction force microscopy with a custom flow chamber to examine how human umbilical vein endothelial cells (HUVECs) adapt their traction during transitions from short-term low shear to long-term high shear stress, compared to direct high shear stress. Our findings reveal that initial low FSS elevates traction to only half the amount observed in response to direct high FSS, even after transitioning to high FSS. However, in the long term under high FSS, starting with low FSS triggers a substantial second rise in traction over 10 hours. Conversely, starting directly with high FSS results in a quick traction surge followed by a significant reduction below baseline traction within 30 minutes. Importantly, the orientation of traction vectors is influenced by the initial shear exposure. Traction aligning in the flow direction under direct high FSS causes cell alignment toward the flow direction, while traction oriented perpendicular to the flow under temporary low FSS causes cell orientation perpendicular to the flow. These traction and cell orientation behaviors are greatly dependent on mechanosensitive ion channels Piezo1, TRPV4, and Kir2.1, which sense the FSS and distinguish between different magnitudes, critically aligning the cells in the direction of the flow. FAK is significantly involved in traction dynamics modulation under high FSS but not under low FSS. These upstream effectors are highly active under high FSS but not under low FSS, where low FSS activates pathways independent of mechanosensitive ion channels and FAK, yet still plays a critical role in EC alignment. These FSS sensing mechanisms provide new insights into how ECs distinguish between FSS magnitudes and underscore their importance in EC remodeling for atheroprotective and atheroprone responses. This study highlights the significant influence of initial short-term low FSS on lasting changes in endothelial traction and cell alignment, contributing to our understanding of endothelial mechanotransduction under varying shear stress conditions.
Recommended Citation
Chandurkar, Mohanish Kishor, "Endothelial Traction Dynamics And Mechanotransduction In Response To Time-Varying Fluid Shear Stress (FSS)", Campus Access Dissertation, Michigan Technological University, 2024.