title: The nucleus of endothelial cell as a sensor of blood flow direction.
abstract: Hemodynamic shear stresses cause endothelial cells (ECs) to polarize in the plane of the flow. Paradoxically, under strong shear flows, ECs disassemble their primary cilia, common sensors of shear, and thus must use an alternative mechanism of sensing the strength and direction of flow. In our experiments in microfluidic perfusion chambers, confluent ECs developed planar cell polarity at a rate proportional to the shear stress. The location of Golgi apparatus and microtubule organizing center was biased to the upstream side of the nucleus, i.e. the ECs polarized against the flow. These in vitro results agreed with observations in murine blood vessels, where EC polarization against the flow was stronger in high flow arteries than in veins. Once established, flow-induced polarization persisted over long time intervals without external shear. Transient destabilization of acto-myosin cytoskeleton by inhibition of myosin II or depolymerization of actin promoted polarization of EC against the flow, indicating that an intact acto-myosin cytoskeleton resists flow-induced polarization. These results suggested that polarization was induced by mechanical displacement of EC nuclei downstream under the hydrodynamic drag. This hypothesis was confirmed by the observation that acute application of a large hydrodynamic force to ECs resulted in an immediate downstream displacement of nuclei and was sufficient to induce persistent polarization. Taken together, our data indicate that ECs can sense the direction and strength of blood flow through the hydrodynamic drag applied to their nuclei.
authors.affiliation: Department of Medicine, University of California-San Diego , La Jolla, CA 92093 , USA ; Department of Physics, University of California-San Diego , La Jolla, CA 92093 , USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Tkachenko
authors.forename: Edgar
authors.initials: E
authors.lastname: Gutierrez
authors.forename: Semion K
authors.initials: SK
authors.lastname: Saikin
authors.forename: Per
authors.initials: P
authors.lastname: Fogelstrand
authors.forename: Chungho
authors.initials: C
authors.lastname: Kim
authors.forename: Alex
authors.initials: A
authors.lastname: Groisman
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
keywords: Endothelium; Mechanotransduction; Nucleus; Planar cell polarity; Shear stress