Ultrastructural Analysis Reveals cAMP-Dependent Enhancement of Microvascular Endothelial Barrier Functions via Rac1-Mediated Reorganization of Intercellular Junctions

Spindler, Volker; Peter, Dominik; Harms, Gregory S.; Asan, Esther; Waschke, Jens

doi:10.1016/j.ajpath.2011.01.014

Cited by 36 publications

(53 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…37 Notably, the only treatments shown to reduce the frequency and severity of SCLS attacks, aside from IVIG, is a regimen of theophylline (phosphodiesterase inhibitor) and terbutaline (␤-adrenergic agonist), 6,38 which are known to promote endothelial barrier function by stabilizing VE-cadherin-mediated adhesive junctions. [39][40][41] Thus, our results could account for the effectiveness of these therapies for SCLS.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome)

Xie

Ghosh

Patel

et al. 2012

Blood

169

208

View full text Add to dashboard Cite

The systemic capillary leak syndrome (SCLS) is a rare disorder characterized by transient episodes of hypotensive shock and anasarca thought to arise from reversible microvascular barrier dysfunction. Although the high prevalence of a monoclonal gammopathy of unknown significance in SCLS suggests a pathogenic contribution of endogenous immunoglobulins, the mechanisms of vascular hyperpermeability remain obscure. Herein, we report clinical and molecular findings on 23 patients, the largest SCLS case series to date. Application of episodic SCLS sera, but neither the purified immunoglobulin fraction nor sera obtained from patients during remission, to human microvascular endothelial cells caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. Intravenous immunoglobulin, one promising therapy for SCLS, mitigated the permeability effects of episodic sera. Consistent with the presence of endogenous, nonimmunoglobulin, circulating permeability factor(s) constrained to SCLS episodes, we found that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Ab-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera.

show abstract

Section: Discussionmentioning

confidence: 99%

Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome)

Xie

Ghosh

Patel

et al. 2012

Blood

169

208

View full text Add to dashboard Cite

show abstract

“…Under resting conditions, these enzymes stabilize the circumferential actin fibers that support robust VE-cadherin adhesions. Activation of Rac1 or Cdc42 have been noted downstream of S1P 7 and cAMP/Rap1 signaling, 8,9 both of which are known to stabilize endothelial cell junctions.…”

Section: Regulation Of Inter-endothelial Adherens Junctions Under Resmentioning

confidence: 98%

Control of vascular permeability by adhesion molecules

Sarelius

Glading²

2014

Tissue Barriers

View full text Add to dashboard Cite

Vascular permeability is a vital function of the circulatory system that is regulated in large part by the limited flux of solutes, water, and cells through the endothelial cell layer. One major pathway through this barrier is via the inter-endothelial junction, which is driven by the regulation of cadherin-based adhesions. The endothelium also forms attachments with surrounding proteins and cells via 2 classes of adhesion molecules, the integrins and IgCAMs. Integrins and IgCAMs propagate activation of multiple downstream signals that potentially impact cadherin adhesion. Here we discuss the known contributions of integrin and IgCAM signaling to the regulation of cadherin adhesion stability, endothelial barrier function, and vascular permeability. Emphasis is placed on known and prospective crosstalk signaling mechanisms between integrins, the IgCAMs- ICAM-1 and PECAM-1, and inter-endothelial cadherin adhesions, as potential strategic signaling nodes for multipartite regulation of cadherin adhesion.

show abstract

“…Furthermore, there are also clear differences in the behavior toward macromolecules, such as low-density lipoproteins (LDLs), between brain endothelial cells and peripheral endothelium (Dehouck et al, 1994). Spindler et al (2011) indicated that cAMP signaling is barrier-protective via Rac1 in microvascular endothelial cells, but not in macrovascular endothelial cells. Our observation may represent an intrinsic difference between brain and peripheral endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…We found that HGF induced F-actin rearrangement and increased the expression of VE-cadherin in RBEC. The rearrangement of cytoskeletal actin fibers is an important factor that affects barrier function of endothelial cells (Lai et al, 2005;Vandenbroucke et al, 2008;Spindler et al, 2011). Accumulating evidence suggests that HGF stimulates multiple signaling pathways, such as small GTPase Rac, MAP, PKC, PI3-kinase, and its downstream effector GSK-3β (Liu et al, 2002;Trusolino et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte growth factor enhances the barrier function in primary cultures of rat brain microvascular endothelial cells

Yamada

Nakagawa

Horai

et al. 2014

Microvascular Research

View full text Add to dashboard Cite

The effects of hepatocyte growth factor (HGF) on barrier functions were investigated by a blood-brain barrier (BBB) in vitro model comprising a primary culture of rat brain capillary endothelial cells (RBEC). In order to examine the response of the peripheral endothelial cells to HGF, human umbilical vascular endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC) were also treated with HGF.HGF decreased the permeability of RBEC to sodium fluorescein and Evans blue albumin, and dose-dependently increased transendothelial electrical resistance (TEER) in RBEC. HGF altered the immunochemical staining pattern of F-actin bands and made ZO-1 staining more distinct on the linear cell borders in RBEC. In contrast, HGF increased sodium fluorescein and Evans blue albumin permeability in HMVEC and HUVEC, and decreased TEER in HMVEC. In HMVEC, HGF reduced cortical actin bands and increased stress fiber density, and increased the zipper-like appearance of ZO-1 staining. Western blot analysis showed that HGF significantly increased the amount of ZO-1 and VE-cadherin. HGF seems to act on the BBB to strengthen BBB integrity. These finding indicated that cytoskeletal rearrangement and cell-cell adhesion, such as through VE-cadherin and ZO-1, are candidate mechanisms for the influence of HGF on the BBB. The possibility that HGF has therapeutic significance in protecting the BBB from damage needs to be considered.

show abstract

Ultrastructural Analysis Reveals cAMP-Dependent Enhancement of Microvascular Endothelial Barrier Functions via Rac1-Mediated Reorganization of Intercellular Junctions

Cited by 36 publications

References 45 publications

Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome)

Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome)

Control of vascular permeability by adhesion molecules

Hepatocyte growth factor enhances the barrier function in primary cultures of rat brain microvascular endothelial cells

Contact Info

Product

Resources

About