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1 Pulmonary and Critical Care Division, Harvard School of Public Health, Boston, MA, USA
2 Environmental Health, BostonTufts-New England Medical Center, Boston, MA, USA
3 Institute of Biochemistry, Medical School Hannover, Hannover, Germany
4 Pulmonary and Critical Care, Johns Hopkins School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: ukayyali{at}tufts-nemc.org.
Hypoxia alters the barrier function of the endothelial cells that line the pulmonary vasculature, but underlying biophysical mechanisms remain unclear. Using rat pulmonary microvascular endothelial cells (RPMEC) in culture, we report changes in biophysical properties, both in space and time, that occur in response to hypoxia. We address also the molecular basis of these changes. At the level of the single cell we measured cell stiffness, the distribution of traction forces exerted by the cell on its substrate, and spontaneous nano-scale motions of microbeads tightly bound to the cytoskeleton (CSK). Hypoxia increased cell stiffness and traction forces by a mechanism that was dependent on the activation of Rho kinase. These changes were followed by p38-mediated decreases in spontaneous bead motions, indicating stabilization of local cell-extracellular matrix (ECM) tethering interactions. Cells overexpressing phospho-mimicking small heat shock protein (HSP27-PM), a downstream effector of p38, exhibited decreases in spontaneous bead motions that correlated with increases in actin polymerization in these cells. Together, these findings suggest that hypoxia differentially regulates endothelial cell contraction and cell-ECM adhesion.
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