Jacobs School of Engineering

Endothelial Cell Remodeling

1. Title: Mechano Transduction on Cell Structure and Signal

Grant Number: BRP081804F

Funding Agency: NIH. Co Investigator with Professor Shu Chien (PI).

The shear stress due to blood flow is borne primarily by endothelial cells (ECs) located at the interface between the blood and vessel wall. Atherosclerotic lesions are preferentially localized in regions such as arterial branch points and local lumen expansions, where the ECs are subjected to disturbed flow conditions, including flow reattachment, low shear stress magnitude, and high shear stress gradient. The ECs in these regions have different structural and functional characteristics in comparison to those in the straight parts of the arterial tree, which are exposed to pulsatile flow with a large net forward direction. Our hypothesis is that flows with a significant net direction cause adaptive changes in cell morphology that reduce surface stress and alter molecular signaling, such that the ECs can optimize their functions. In contrast, disturbed flows, without a significant net direction, do not elicit the same adaptive effects on EC surface stress distribution and lead to different spatial and temporal characteristics of molecular signaling, structural remodeling, and mechanical properties, thus resulting in distinct functional consequences such as vulnerability to atherosclerosis.  We are testing this hypothesis using a combination of in vitro and in vivo approaches to determine the effects of different shear flow patterns on surface stress and structural remodeling of ECs. The results of this work have been published in a paper in the Proceedings of the American Academy of Sciences (I-75).

2. Title: Mechanical and Molecular Bases of Endothelial Remodeling

Grant Number: 1RO1 HL0805518

Funding Agency: NIH. Co Investigator with Professor Shu Chien (PI).

Vascular endothelial cells are constantly subjected to cyclical stretch due to the pulsatile pressure of the blood flow. In straight, un-branched arteries, the EC elongate with their major axis oriented parallel to the mean flow direction and perpendicular to the direction of stretch. Actin fibers aligned perpendicular to stretch bear less tension than when they are aligned parallel to the stretch. Thus, perpendicular orientation of the actin fiber serves to reduce the mechanical energy absorbed by the cell with each stretch cycle. We are exploring a possible mechanical and molecular feedback control for EC adaptation to mechanical stimulation. We hypothesize that the feedback control is regulated by energy minimization resulting from EC stretch fiber remodeling.  We have shown that ECs remodel their cytoskeleton, including its directionality, in response to mechanical stimuli with consequent redistribution of intracellular forces and modulation of cell function. We use tracking microrheology to determine the principal directions along which the creep compliance G is maximal and minimal at each point in the cytoplasm. We show that after continuous flow shear stresses, all cells gradually elongate and the directions of maximal and minimal G become, respectively, parallel and perpendicular to the flow direction.

Related Papers

PDFJ.C. Del Álamo, G. Norwich, Y.S. Li, J.C. Lasheras and S. Chien. "Anisotropic Rheology and Directional Mechanotransduction in Vascular Endothelial Cells." Proc. Nat. Acad. Sciences of the USA. Vol. 105, No. 40. pp.15411-15416, (2008).

PDFS.S. Hur, J.C. Del Álamo, Y.S. Li, J.S. Park, J.C. Lasheras and S. Chien. "Roles of Cell Confluency and Fluid Shear in 3-Dimensional Intracellular Forces In Endothelial Cells." Proc. Nat. Acad. Sciences of the USA. Vol. 109, Number 28. pp. 11110-11115 (2012).

PDFH-H Lee, H-C Lee, C-C Chou, S.S. Hur, K. Osterday, J.C. Del Álamo, J.C. Lasheras and S. Chien. "Shp2 Modulates Intracellular Tension Through Regulating ROCK-mediated Focal Adhesion Maturation in Response to Matrix Rigidity." Proc. Nat. Acad. Sciences of the USA. In press (2013).