PDCD10 (CCM3) regulates brain endothelial barrier integrity in cerebral cavernous malformation type 3: role of CCM3-ERK1/2-cortactin cross-talk

Stamatovic, Svetlana M.; Sladojević, Nikola; Keep, Richard F.; Andjelkovic, Anuska V.

doi:10.1007/s00401-015-1479-z

Cited by 45 publications

(59 citation statements)

References 77 publications

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“…143 The polyubiquitination of claudin-5 (Lys-199), ZO-1, Ve-cadherin, JAM-A, cortactin and particularly connexins trigger junction protein proteasome-dependent degradation and serve as a mechanism of protein turnover and junction complex remodeling. 65,[144][145][146][147] So far, the ubiquitination and proteasomal degradation of occludin is the only one described as an underlying mechanism of BBB dysfunction in permanent brain ischemia.…”

Section: Degradation Of Junction Proteins and Bbb Dysfunctionmentioning

confidence: 99%

“…120,121 Phosphorylation of cortactin on Ser-405 resides leads to dissociation of cortactin from ZO-1 and contributes to disassembly of TJ complex in CCM3 lesions. 65 Changes in connexin phosphorylation status are closely associated with changes in GJ assembly, stability and channel properties. Both phosphorylation and dephosphorylation regulate connexin function.…”

Section: Phosphorylationmentioning

confidence: 99%

“…42,47 Among the actin polymerizing proteins associated with TJs and expressed in brain endothelial cells are Arp2/3, cortactin and VASP. [64][65][66] The regulation of actin organization and trafficking is mediated by RhoA GTPases (RhoA, Cdc42 and Rac) and the Rab family of proteins and these proteins are closely associated with TJ complex acting via their exchanging factors as scaffolding proteins. 55,56,67,68 Other actin binding proteins involved in linking ZO-1 and actin filaments are actin-crosslinking protein, a-actinin-4, vinculin, actin/spectrin interacting protein 4.1 and anillin, but their expression in brain endothelial cells is still not confirmed.…”

Section: Actin Binding Proteins and Actin Filamentsmentioning

confidence: 99%

“…This consequently induces disassembly of the TJ complex by redistribution of claudin-5 and occludin from the cell membrane. 65 Any of the CCM mutations cause increased BBB permeability over time. Chronic hyperpermeability represents a solid base for developing dilated vessels, accumulation of inflammatory cells and, over time, hemorrhagic transformation.…”

Section: -81mentioning

confidence: 99%

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Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

et al. 2016

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Section: Degradation Of Junction Proteins and Bbb Dysfunctionmentioning

confidence: 99%

Section: Phosphorylationmentioning

confidence: 99%

Section: Actin Binding Proteins and Actin Filamentsmentioning

confidence: 99%

Section: -81mentioning

confidence: 99%

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Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

et al. 2016

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“…Claudins and occludin are stabilized by intracellular adaptor proteins, including zonula occludens 1 (ZO‐1), that tether them to the actin cytoskeleton. Analysis of TJ proteins in lesions of patients with fCCM3 and in vitro work has demonstrated a loss of TJ proteins from the junctional complex of fCCM3 (4, 5). Meanwhile, whether adherens junctions, organized in a similar manner to TJs with transmembrane cadherins and adapter proteins, are affected in fCCM3 is less clear (4, 6).…”

mentioning

confidence: 99%

Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure

Johnson

Roach

et al. 2018

FASEB j.

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Familial cerebral cavernous malformations type III (fCCM3) is a disease of the cerebrovascular system caused by loss-of-function mutations in ccm3 that result in dilated capillary beds that are susceptible to hemorrhage. Before hemorrhage, fCCM3 lesions are characterized by a hyperpermeable blood-brain barrier (BBB), the key pathologic feature of fCCM3. We demonstrate that connexin 43 (Cx43), a gap junction (GJ) protein that is incorporated into the BBB junction complex, is up-regulated in lesions of a murine model of fCCM3. Small interfering RNA-mediated ccm3 knockdown (CCM3KD) in brain endothelial cells in vitro increased Cx43 protein expression, GJ plaque size, GJ intracellular communication (GJIC), and barrier permeability. CCM3KD hyperpermeability was rescued by GAP27, a peptide gap junction and hemichannel inhibitor of Cx43 GJIC. Tight junction (TJ) protein, zonula occludens 1 (ZO-1), accumulated at Cx43 GJs in CCM3KD cells and displayed fragmented staining at TJs. The GAP27-mediated inhibition of Cx43 GJs in CCM3KD cells restored ZO-1 to TJ structures and reduced plaque accumulation at Cx43 GJs. The TJ protein, Claudin-5, was also fragmented at TJs in CCM3KD cells, and GAP27 treatment lengthened TJ-associated fragments and increased Claudin 5-Claudin 5 transinteraction. Overall, we demonstrate that Cx43 GJs are aberrantly increased in fCCM3 and regulate barrier permeability by a TJ-dependent mechanism.-Johnson, A. M., Roach, J. P., Hu, A., Stamatovic, S. M., Zochowski, M. R., Keep, R. F., Andjelkovic, A. V. Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure.

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Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth

Sone

Hobson

Srinath

et al. 2021

Magnetic Resonance Imaging

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Background Cerebral cavernous angioma (CA) is a capillary vasculopathy affecting more than a million Americans with a small fraction of cases demonstrating lesional bleed or growth with major clinical sequelae. Perfusion and permeability are fundamental features of CA pathophysiology, but their role as prognostic biomarkers is unclear. Purpose To investigate whether perfusion or permeability lesional descriptors derived from dynamic contrast‐enhanced quantitative perfusion (DCEQP) magnetic resonance imaging (MRI) can predict subsequent lesional bleed/growth in the year following imaging. Study Type Single‐site case‐controlled study. Subjects Two hundred and five consecutively enrolled patients (63.4% female). Field Strength/Sequence Three‐Tesla/T1‐mapping with contrast‐enhanced dynamic two‐dimensional (2D) spoiled gradient recalled acquisition (SPGR) sequences. Assessment Prognostic associations with bleed/growth (present or absent) in the following year were assessed in 745 CA lesions evaluated by DCEQP in the 205 patients in relation to lesional descriptors calculated from permeability and perfusion maps. A subgroup of 30 cases also underwent peripheral blood collection at the time of DCEQP scans and assays of plasma levels of soluble CD14, IL‐1β, VEGF, and soluble ROBO4 proteins, whose weighted combination had been previously reported in association with future CA bleeding. Statistical Tests Mann–Whitney U‐test for univariate analyses. Logistic regression models minimizing the Bayesian information criterion (BIC), testing sensitivity and specificity (receiver operating characteristic curves) of weighted combinations of parameters. Results The best prognostic biomarker for lesional bleed or growth included brainstem lesion location, mean lesional permeability, and low‐value perfusion cluster mean (BIC = 201.5, sensitivity = 77%, specificity = 72%, P < 0.05). Adding a previously published prognostic plasma protein biomarker improved the performance of the imaging model (sensitivity = 100%, specificity = 88%, P < 0.05). Data Conclusion A combination of MRI‐based descriptors reflecting higher lesional permeability and lower perfusion cluster may potentially predict future bleed/growth in CAs. The sensitivity and specificity of the prognostic imaging biomarker can be enhanced when combined with brainstem lesion location and a plasma protein biomarker of CA hemorrhage. Level of Evidence 2 Technical Efficacy Stage 5

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PDCD10 (CCM3) regulates brain endothelial barrier integrity in cerebral cavernous malformation type 3: role of CCM3-ERK1/2-cortactin cross-talk

Cited by 45 publications

References 77 publications

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure

Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth

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