Signal transduction and regulation of lung endothelial cell permeability. Interaction between calcium and cAMP

Abstract

Pulmonary endothelium forms a semiselective barrier that regulates fluid balance and leukocyte trafficking. During the course of lung inflammation, neurohumoral mediators and oxidants act on endothelial cells to induce intercellular gaps permissive for transudation of proteinaceous fluid from blood into the interstitium. Intracellular signals activated by neurohumoral mediators and oxidants that evoke intercellular gap formation are incompletely understood. Cytosolic Ca2+ concentration ([Ca2+]i) and cAMP are two signals that importantly dictate cell-cell apposition. Although increased [Ca2+]ipromotes disruption of the macrovascular endothelial cell barrier, increased cAMP enhances endothelial barrier function. Furthermore, during the course of inflammation, elevated endothelial cell [Ca2+]idecreases cAMP to facilitate intercellular gap formation. Given the significance of both [Ca2+]iand cAMP in mediating cell-cell apposition, this review addresses potential sites of cross talk between these two intracellular signaling pathways. Emerging data also indicate that endothelial cells derived from different vascular sites within the pulmonary circulation exhibit distinct sensitivities to permeability-inducing stimuli; that is, elevated [Ca2+]ipromotes macrovascular but not microvascular barrier disruption. Thus this review also considers the roles of [Ca2+]iand cAMP in mediating site-specific alterations in endothelial permeability.

Spatial coordination between cell and nuclear shape within micropatterned endothelial cells

“…To control both the cell shape index (CSI) and the SA of single ECs, we used a microcontact printing technique to pattern FN 30 and define adherent cell shapes and SAs (from 600 to 2,000 µm 2 ). We shapeengineered ECs on circular (CSI = 1), square (CSI = 0.79) and various rectangular (CSI = 0.70, 0.50 and 0.26) adhesive micropatterns, mimicking elongated bipolar shapes observed in vivo [5][6][7] . To investigate whether large-scale changes of cell morphology could influence nuclear morphology, we assessed the CSI by differential interference contrast (DIC) microscopy and the nuclear shape index (NSI) by 4′,6-diamidino-2-phenylindole (DAPI) staining for 1,600 µm 2 shaped cells (Fig.…”

“…For instance, it is well known that the formation of new blood capillaries requires the polarization and directed migration of endothelial cells (ECs) through large cell elongations [5][6][7][8][9] . In addition, cell shape changes in ECs are commonly associated with nuclear shape remodelling [10][11][12][13] , which is emerging as a potential regulator of genome function [14][15][16] .…”

“…This problem can be tackled non-invasively by the use of adhesive islands to create a spatial environment that force single ECs to elongate, up to large-scale changes as observed in vivo [5][6][7] . We used in this study fibronectin (FN)-coated micropatterns of defined shapes and sizes to understand how changes in cell shape and spreading area (SA), which is known to be a key parameter of the cellular mechanical force balance 28,29 , induce cytoskeletal reorganizations that regulate the nuclear shape.…”

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

“…In pulmonary endothelium (30,44,46,55,56) and epithelium (36), PDE2A, 3, 4, and 5 appear to represent the most significant forms. PDE2A is a dual-function PDE capable of hydrolyzing both cAMP and cGMP.…”

Cyclic AMP Phosphodiesterase 4D (PDE4D) Tethers EPAC1 in a Vascular Endothelial Cadherin (VE-Cad)-based Signaling Complex and Controls cAMP-mediated Vascular Permeability

“…By increasing the integrity of VE-Cad-based adhesions and promoting their interactions with the actin cytoskeleton, activators of cAMP signaling decrease basal VEC permeability and antagonize the effects of VEGF (11)(12)(13)(14)(15). These barrier-stabilizing effects of activators of cAMP signaling are coordinated through effects by either protein kinase A (PKA) or exchange protein activated by cAMP (EPAC).…”