Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases

Luo, Min; Flood, Elle C.; Almeida, Dena; Yan, LunBiao; Berlin, David; Heerdt, Paul M.; Hajjar, Katherine A.

doi:10.1084/jem.20160652

Cited by 35 publications

(41 citation statements)

References 27 publications

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“…Consistently, an earlier study reported that AnxA2 expression was increased after traumatic spinal cord injury [17]. The most important finding of the present study is the association of AnxA2 deficiency with the increased leukocyte brain infiltration, which is consistent with previous studies showing that A2KO mice exhibit increased pulmonary neutrophil infiltration in polymicrobial sepsis models [14] as well as in response to subacute alveolar hypoxia [18] compared to WT mice. Two potential mechanisms are underlying the role of AnxA2 in regulating leukocytes brain infiltration.…”

Section: Discussionsupporting

confidence: 93%

“…Secondly, the increased leukocytes infiltration might also be at least partially attributed by the BBB integrity disruption in the A2KO mice. There were previous reports of increased pulmonary neutrophil infiltration in A2KO mice during alveolar hypoxia, which is associated with a reduced endothelial barrier function compared to the WT mice [18]. Moreover, we recently reported that A2KO mice compromise brain microvascular integrity [16].…”

Section: Discussionmentioning

confidence: 84%

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Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

Liu

Jiang

Chung

et al. 2019

IJMS

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Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 84%

Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

Liu

Jiang

Chung

et al. 2019

IJMS

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“…Microvascular endothelial cells deficient in annexin A2 exhibit reduced barrier function. 21 Annexin A2edeficient mice develop more substantial vascular leak, pulmonary edema, and neutrophil infiltration in response to alveolar injury compared with control mice. 21 Annexin A2 can bind to actin and bundle actin filaments through residues on its C-terminus, and it also interacts directly with VE-cadherin in endothelial cells.…”

mentioning

confidence: 98%

Endothelial Cell Calcium Signaling during Barrier Function and Inflammation

Dalal

Müller

Sullivan

2020

The American Journal of Pathology

155

112

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Calcium is an essential second messenger in endothelial cells and plays a pivotal role in regulating a number of physiologic processes, including cell migration, angiogenesis, barrier function, and inflammation. An increase in intracellular Ca 2þ concentration can trigger a number of diverse signaling pathways under both physiologic and pathologic conditions. In this review, we discuss how calcium signaling pathways in endothelial cells play an essential role in affecting barrier function and facilitating inflammation. Inflammatory mediators, such as thrombin and histamine, increase intracellular calcium levels. This calcium influx causes adherens junction disassembly and cytoskeletal rearrangements to facilitate endothelial cell retraction and increased permeability. During inflammation endothelial cell calcium entry and the calcium-related signaling events also help facilitate several leukocyteeendothelial cell interactions, such as leukocyte rolling, adhesion, and ultimately transendothelial migration.

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“…While the roles of EPAC signaling in modulating endothelial barrier functions and inflammatory response have been examined extensively (22,23), studies and information related to cAMP's functions in fibrinolysis are scarce. Our current study reveals that EPAC1 interacts with AnxA2, a phospholipid binding protein abundantly expressed in endothelial cells and important for vascular fibrinolysis and integrity (24,25). This unexpected finding led us to investigate the physiological functions of EPAC1:AnxA2 interaction.…”

Section: Discussionmentioning

confidence: 60%

EPAC1 regulates endothelial Annexin A2 cell surface translocation and plasminogen activation

Mei

Cheng

2017

Preprint

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Annexins, a family of highly conserved calcium-and phospholipid-binding proteins, play important roles in a wide range of physiological functions. Among the twelve known annexins in human, Annexin A2 (AnxA2) is one of the most extensively studied and has been implicated in various human diseases. AnxA2 can exist as a monomer or a heterotetrameric complex with S100A10 (P11) and plays a critical role in many cellular processes including exocytosis/endocytosis and membrane organization. At the endothelial cell surface, (AnxA2•P11)2 tetramer, acting as a coreceptor for plasminogen and tissue plasminogen activator (t-PA), accelerates t-PA dependent activation of the fibrinolytic protease, plasmin, the enzyme responsible for thrombus dissolution and degradation of fibrin. This study shows that exchange proteins directly activated by cAMP isoform 1 (EPAC1) interacts with AnxA2 and regulates its biological functions by modulating its membrane translocation in endothelial cells. Using genetic and pharmacological approaches, it is demonstrated that EPAC1, acting through the PLCε-PKC pathway, inhibits AnxA2 surface translocation and plasminogen activation. These results suggest that EPAC1 plays a role in the regulation of fibrinolysis in endothelial cells and may represent a novel therapeutic target for disorders of fibrinolysis.

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Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases

Abstract: Luo et al. demonstrate that annexin A2 is required to maintain vascular integrity in the hypoxic mouse lung. A2 prevents extravasation of fluid and leukocytes by promoting activity of the phosphatases VE-PTP and SHP2, thereby modulating phosphorylation of vascular endothelial cadherin.

Cited by 35 publications

References 27 publications

Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

Endothelial Cell Calcium Signaling during Barrier Function and Inflammation

EPAC1 regulates endothelial Annexin A2 cell surface translocation and plasminogen activation

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