Involvement of the H1 Histamine Receptor, p38 MAP Kinase, Myosin Light Chains Kinase, and Rho/ROCK in Histamine‐Induced Endothelial Barrier Dysfunction

During inflammation, the disruption of the endothelial barrier leads to increased microvascular permeability. Whether tension along cell junctions contributes to histamine-induced endothelial barrier disruption remains unknown. Rapid Ca2+ influx induced by both histamine and thrombin was accompanied by endothelial barrier breakdown revealed as drop of transendothelial electric resistance in primary human microvascular endothelial cells. Interestingly, GLISA measurements revealed activation of RhoA but not inactivation of Rac1 at the time-point of barrier breakdown. FRET measurements showed activation of RhoA at intercellular junctions after both thrombin and histamine exposure. Breakdown coincided with increased stress fiber formation but not with translocation of vinculin, which was located along junctions in the resting state similar to postcapillary venules ex vivo. Moreover, increased tension at AJs was indicated by immunostaining with a conformation-sensitive antibody targeting the α18-subunit of α-catenin. Ca2+ chelation by BAPTA-AM and ROCK1 inhibition by Y27632 abolished both increase of tension along AJs as well as barrier dysfunction. Moreover, BAPTA-AM decreased RhoA activation following histamine stimulation, indicating a key role of Ca2+ signaling in barrier breakdown. Taken together, in response to histamine, Ca2+ via RhoA/ROCK activation along endothelial adherens junctions (AJs) appears to be critical for barrier disruption and presumably correlated with enhanced tension. However, vinculin appears not to be critical in this process.

show abstract

“…RhoA can be activated independently by H1R coupled to G q/11 28 . H1R also leads to an increase of intracellular Ca 2+ concentration.…”

Section: Discussionmentioning

confidence: 99%

Histamine causes endothelial barrier disruption via Ca2+-mediated RhoA activation and tension at adherens junctions

Kugelmann

Rotkopf

Radeva

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…2A, arrowheads), revealed that histamine significantly increased the lateral velocity of these actin fibers toward the center of the cell (Fig. In addition, this elevated number of actin fibers occurred after the reported histamine-induced increases in permeability have already recovered to baseline (2,27). 2C).…”

Section: Resultsmentioning

confidence: 83%

“…1A and Supplemental Video S1; supplemental material for this article is available online at the Journal website). This rapid response occurs within the time frame when histamine typically disrupts the endothelial barrier in HUVEC (2,20,27). 1B), but there was no significant impact on protrusion persistence or protrusion velocity.…”

Section: Resultsmentioning

confidence: 89%

“…We recently demonstrated the importance of p38 MAP kinase for histamine-induced endothelial barrier dysfunction in both HUVEC and microvascular endothelial cell monolayers (2). We recently demonstrated the importance of p38 MAP kinase for histamine-induced endothelial barrier dysfunction in both HUVEC and microvascular endothelial cell monolayers (2).…”

Section: Resultsmentioning

confidence: 98%

See 1 more Smart Citation

Histamine activates p38 MAP kinase and alters local lamellipodia dynamics, reducing endothelial barrier integrity and eliciting central movement of actin fibers

Adderley

Lawrence

Madonia

et al. 2015

American Journal of Physiology-Cell Physiology

Self Cite

View full text Add to dashboard Cite

The role of the actin cytoskeleton in endothelial barrier function has been debated for nearly four decades. Our previous investigation revealed spontaneous local lamellipodia in confluent endothelial monolayers that appear to increase overlap at intercellular junctions. We tested the hypothesis that the barrier-disrupting agent histamine would reduce local lamellipodia protrusions and investigated the potential involvement of p38 mitogen-activated protein (MAP) kinase activation and actin stress fiber formation. Confluent monolayers of human umbilical vein endothelial cells (HUVEC) expressing green fluorescent protein-actin were studied using time-lapse fluorescence microscopy. The protrusion and withdrawal characteristics of local lamellipodia were assessed before and after addition of histamine. Changes in barrier function were determined using electrical cell-substrate impedance sensing. Histamine initially decreased barrier function, lamellipodia protrusion frequency, and lamellipodia protrusion distance. A longer time for lamellipodia withdrawal and reduced withdrawal distance and velocity accompanied barrier recovery. After barrier recovery, a significant number of cortical fibers migrated centrally, eventually resembling actin stress fibers. The p38 MAP kinase inhibitor SB203580 attenuated the histamine-induced decreases in barrier function and lamellipodia protrusion frequency. SB203580 also inhibited the histamine-induced decreases in withdrawal distance and velocity, and the subsequent actin fiber migration. These data suggest that histamine can reduce local lamellipodia protrusion activity through activation of p38 MAP kinase. The findings also suggest that local lamellipodia have a role in maintaining endothelial barrier integrity. Furthermore, we provide evidence that actin stress fiber formation may be a reaction to, rather than a cause of, reduced endothelial barrier integrity.

show abstract

“…Downstream signals such as eNOS-mediated NO release, cGMP production by guanylate cyclase, and PKG activation have also been implicated (Yuan et al , 1992; Yuan et al , 1993b; Wu et al , 1996; Varma et al , 2002; Breslin et al , 2003; Sanchez et al , 2006; Durán et al , 2008; Sánchez et al , 2009; Duran et al , 2010; Sánchez et al , 2011). Other notable signaling pathways that contribute to microvascular hyperpermeability include activation of Src (Eliceiri et al , 1999; Kevil et al , 2001; Paul et al , 2001; Tinsley et al , 2002) and the MAP kinase cascades including ERK-1/2 and p38 MAP kinase (Kevil et al , 1998; Kevil et al , 2000; Verin et al , 2000; Becker et al , 2001; Lal et al , 2001; Garcia et al , 2002; Nwariaku et al , 2002; Varma et al , 2002; Breslin et al , 2003; Aramoto et al , 2004; Wu et al , 2005; Yu et al , 2005a; Adderley et al , 2015a; Adderley et al , 2015b). Additional signaling molecules that more directly impact the activity and conformation of the actin cytoskeleton have also been shown to have importance.…”

Section: Determinants Of Endothelial Barrier Functionmentioning

confidence: 99%

Endothelial Protrusions in Junctional Integrity and Barrier Function

Alves

Motawe

Yuan

et al. 2018

Current Topics in Membranes

Self Cite

View full text Add to dashboard Cite

Endothelial cells of the microcirculation form a semi-permeable diffusion barrier between the blood and tissues. This permeability of the endothelium, particularly in the capillaries and postcapillary venules, is a normal physiological function needed for blood-tissue exchange in the microcirculation. During inflammation, microvascular permeability increases dramatically and can lead to tissue edema, which in turn can lead to dysfunction of tissues and organs. The molecular mechanisms that control the barrier function of endothelial cells have been under investigation for several decades, and remain an important topic due to the potential for discovery of novel therapeutic strategies to reduce edema. This review highlights current knowledge of the cellular and molecular mechanisms that lead to endothelial hyperpermeability during inflammatory conditions associated with injury and disease. This includes a discussion of recent findings demonstrating temporal protrusions by endothelial cells that may contribute to intercellular junction integrity between endothelial cells and affect the diffusion distance for solutes via the paracellular pathway.

show abstract

Involvement of the H1 Histamine Receptor, p38 MAP Kinase, Myosin Light Chains Kinase, and Rho/ROCK in Histamine‐Induced Endothelial Barrier Dysfunction

Cited by 40 publications

References 64 publications

Histamine causes endothelial barrier disruption via Ca2+-mediated RhoA activation and tension at adherens junctions

Histamine causes endothelial barrier disruption via Ca2+-mediated RhoA activation and tension at adherens junctions

Histamine activates p38 MAP kinase and alters local lamellipodia dynamics, reducing endothelial barrier integrity and eliciting central movement of actin fibers

Endothelial Protrusions in Junctional Integrity and Barrier Function

Contact Info

Product

Resources

About