Abstract 515: Aldosterone Modulates Endothelial Paracellular Permeability by Opening Intercellular Junctions
Aldosterone (Ald) is involved in vascular remodeling and inflammation; however, the mechanisms are imperfectly defined. We hypothesized that Ald alters endothelial integrity and modifies paracellular permeability. Human umbilical vein endothelial cells (HUVEC) were exposed to Ald (10-9 mol/L) and alterations in paracellular permeability, assembly of tight and adherens junctions, and activation of intracellular signaling pathways were determined. Ald increased endothelial paracellular permeability for molecules up to 70 kDa within 60 min. A transient loss of cortical actin with formation of actin stress fibers, and disruption of continuous adherens and tight junction strands, accompanied the changes. Mineralocorticoid receptor (MR) blockade, inhibition of RhoA or disruption of extracellular regulated protein kinase (ERK) 1/2 signaling pathways attenuated the Ald-related effects. Moreover, the observed changes of the actin cytoskeleton and intercellular junction architecture were accompanied by a rapid dephosphorylation of protein kinase B (AKT) as well as deactivation of endothelial NO synthase (eNOS). Ex vivo tracer flux experiments with Evans Blue (EB)-conjugated albumin demonstrated concordant response to Ald in freshly isolated umbilical arteries. In summary, Ald leads to increased permeability of endothelial monolayer or isolated arteries. These alterations are associated with a temporal opening of Intercellular junctions and diminished eNOS activity, and depend on activation of the RhoA/ERK pathway. We conclude that these mechanisms could contribute to Ald-induced vasculopathy.
- © 2012 by American Heart Association, Inc.