Upregulation of transmembrane endothelial junction proteins in human cerebral cavernous malformations

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>Cerebral cavernous malformations (CCMs) are among the most prevalent cerebrovascular malformations, and endothelial cells seem to play a major role in the disease. However, the underlying mechanisms, including endothelial intercellular communication, have not yet been fully elucidated. In this article, the authors focus on the endothelial junction proteins CD31, VE-cadherin, and occludin as important factors for functional cell-cell contacts known as vascular adhesion molecules and adherence and tight junctions.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Thirteen human CCM specimens and 6 control tissue specimens were cryopreserved and examined for the presence of VE-cadherin, occludin, and CD31 by immunofluorescence staining. Protein quantification was performed by triplicate measurements using western blot analysis.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Immunofluorescent analyses of the CCM sections revealed a discontinuous pattern of dilated microvessels and capillaries as well as increased expression of occludin, VE-cadherin, and CD31 in the intima and in the enclosed parenchymal tissue compared with controls. Protein quantification confirmed these findings by showing upregulation of the levels of these proteins up to 2–6 times.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>A protocol enabling the molecular and morphological examination of the intercellular contact proteins in human CCM was validated. The abnormal and discontinuous pattern in these endothelial cell–contact proteins compared with control tissue explains the loose intercellular junctions that are considered to be one of the causes of CCM-associated bleeding or transendothelial oozing of erythrocytes. Despite the small number of specimens, this study demonstrates for the first time a quantitative analysis of endothelial junction proteins in human CCM.</jats:p></jats:sec>

Bleeding propensity of cavernous malformations: impact of tight junction alterations on the occurrence of overt hematoma

“…8,9,28,31 In all specimens we identified a decrease of TJ immunoreactivity in CMs, either completely or with focally preserved TJ staining, as found in the previous study by our group. 26 Thus, absence of TJ protein staining (Fig.…”

“…Among the vessel wall structures evaluated for a possible role in CM bleeding propensity are the tight junctions between endothelial cells. 8,9,26,28,31 In the present study we evaluated the clinical significance of two TJ alteration patterns with reference to the known hemorrhage prognostic factors as well as the differences in their impact on CM hemorrhage rate.…”

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

“…86 The brain endothelial barrier is abnormal in CCM and characterized by a discontinuous pattern of endothelial cell-cell protein contacts despite a varying production of tight and adherens junction proteins. 87,88 These 3 proteins appear to interact with cytoskeletal and interendothelial cell junction proteins generating a typical pathological substrate for CCMs: alterations in the permeability of the microvasculature and the BBB. Based on experimental and clinical data, CCM1-2 proteins are physically associated in a protein complex, which is required for correct protein localization at endothelial cell-cell junctions.…”

Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management

“…In addition, the formation of microgaps at the interendothelial junction sites was observed using scanning electron microscopy. 52, 53 Zhao et al 54 suggested that CCM may develop as a result of irregular organization of endothelial cells, as a consequence of an increased proliferation and migration potential of these cells. In line with this hypothesis, increased migratory and proliferatory endothelial cell function would indeed require reduced cell-cell contact and reduced presence of pericytes.…”

“…83,84 Treatment with antiplatelet drugs should be avoided, whereas anticoagulation with coumadin derivatives is contra-indicated . 2,19,53 Prognosis of CCMs The long-term prognosis of familial CCM is not well known, but the available data suggest that it is quite favourable after (surgical) treatment.…”