Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

Zhu, Qinglin; Yamakuchi, Munekazu; Ture, Sara; García-Hernández, María de la Luz; Ko, Kyung Ae; Modjeski, Kristina L.; LoMonaco, Michael B.; Johnson, Andrew D.; O’Donnell, Christopher J; Takai, Yoshimi; Morrell, Craig N.; Lowenstein, Charles J.

doi:10.1172/jci71245

Cited by 73 publications

(91 citation statements)

References 88 publications

(128 reference statements)

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“…The reports by Ye et al and Zhu et al (7,8) extend previous observations of a genetic association among STXBP5, plasma levels of vWF, and venous thrombosis risk. These two studies revealed that STXBP5 regulates exocytosis from endothelial cells and platelets, but the influence is disIn Stxbp5 KO mice, plasma levels of vWF were increased, consistent with the demonstrated STXBP5-dependent inhibition of endothelial vWF exocytosis.…”

Section: Discussionsupporting

confidence: 74%

“…The studies by Ye et al (7) and Zhu et al (8) build upon the consistent identification of STXBP5 as a contributor to the regulation of plasma vWF levels (9-11) and as a risk factor for venous thrombosis (12), which suggests that STXBP5 function is important for maintaining normal hemostatic balance (Figure 1). In further support of this notion, a nonsynonymous STXBP5 SNP, N436S, is associated with a decreased incidence of venous thromboembolism (9) and an increased bleeding phenotype in females (13 (7), whereas Zhu and colleagues identified STXBP5 in endothelial cells through its interaction with syntaxin-4, a component of SNARE complexes, and synaptotagmin, the sensor for mediating calcium-induced exocytosis (8). These findings confirmed prior observations in neurons (14) and pancreatic β cells (15) that STXBP5 can form complexes with SNARE proteins and is thus well situated to regulate the exocytic process.…”

Section: Stxbp5 As a Regulator Of Cardiovascular Homeostasismentioning

confidence: 89%

“…Zhu and colleagues demonstrated that STXBP5 also inhibits exocytosis in endothelial cells (8). STXBP5 knockdown in endothelial cells resulted in increased histamine-and calcium ionophore-mediated secretion of vWF and increased externalization of the adhesion molecule P-selectin.…”

Section: Stxbp5 Inhibits Exocytosis In Endothelial Cellsmentioning

confidence: 99%

“…Numbers of α and dense granules in Stxbp5 KO mice were normal, as were platelet counts. Both Ye et al and Zhu et al observed an increase in tail bleeding and defective thrombus generation in Stxbp5 KO mice (7,8). To test whether this defect was the result of a platelet-specific influence, bone marrow transplant experiments were performed.…”

Section: Stxbp5 Inhibits Exocytosis In Endothelial Cellsmentioning

confidence: 99%

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Syntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and platelets

Lillicrap¹

2014

J. Clin. Invest.

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Section: Discussionsupporting

confidence: 74%

Section: Stxbp5 As a Regulator Of Cardiovascular Homeostasismentioning

confidence: 89%

Section: Stxbp5 Inhibits Exocytosis In Endothelial Cellsmentioning

confidence: 99%

Section: Stxbp5 Inhibits Exocytosis In Endothelial Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Syntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and platelets

Lillicrap¹

2014

J. Clin. Invest.

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“…Previous studies have identified proteins that mediate the regulated exocytosis in ECs: for example, vesicle-associated membrane protein (VAMP) 3 (15), VAMP8 (15), syntaxin 4 (15), syntaxin-binding protein 5 (16), and synaptosomal-associated protein 23 (SNAP23) (17). Most of them belong to a superfamily of transmembrane proteins named SNAREs that mediate trafficking of cellular materials between intracellular compartments.…”

mentioning

confidence: 99%

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Zhu

Liu

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Vascular endothelial cells (ECs) at arterial branches and curvatures experience disturbed blood flow and induce a quiescent-to-activated phenotypic transition of the adjacent smooth muscle cells (SMCs) and a subsequent smooth muscle hyperplasia. However, the mechanism underlying the flow pattern-specific initiation of EC-to-SMC signaling remains elusive. Our previous study demonstrated that endothelial microRNA-126-3p (miR-126-3p) acts as a key intercellular molecule to increase turnover of the recipient SMCs, and that its release is reduced by atheroprotective laminar shear (12 dynes/cm 2 ) to ECs. Here we provide evidence that atherogenic oscillatory shear (0.5 ± 4 dynes/cm 2 ), but not atheroprotective pulsatile shear (12 ± 4 dynes/cm 2 ), increases the endothelial secretion of nonmembrane-bound miR-126-3p and other microRNAs (miRNAs) via the activation of SNAREs, vesicleassociated membrane protein 3 (VAMP3) and synaptosomalassociated protein 23 (SNAP23). Knockdown of VAMP3 and SNAP23 reduces endothelial secretion of miR-126-3p and miR-200a-3p, as well as the proliferation, migration, and suppression of contractile markers in SMCs caused by EC-coculture. Pharmacological intervention of mammalian target of rapamycin complex 1 in ECs blocks endothelial secretion and EC-to-SMC transfer of miR-126-3p through transcriptional inhibition of VAMP3 and SNAP23. Systemic inhibition of VAMP3 and SNAP23 by rapamycin or periadventitial application of the endocytosis inhibitor dynasore ameliorates the disturbed flow-induced neointimal formation, whereas intraluminal overexpression of SNAP23 aggravates it. Our findings demonstrate the flow-pattern-specificity of SNARE activation and its contribution to the miRNA-mediated EC-SMC communication. T he interaction between hemodynamics and vascular endothelium is an important determinant of vascular homeostasis (1). In the straight part of the arteries, endothelial cells (ECs) are exposed to laminar blood flow with high shear stress that protects these parts of the vessels from atherogenesis, whereas in the branches and curvatures, the ECs experiencing disturbed flow with reciprocating and low shear stress stimulate the smooth muscle cells (SMCs) within the tunica media to become proliferative and migratory. The activated SMCs migrate into the intima, where they come into close contact with ECs and undergo phenotypic changes to lead to atherosclerosis (2). We recently demonstrated that vascular ECs repress expressions of forkhead box O3, B-cell lymphoma 2, and insulin receptor substrate 1 in the adjacent SMCs by producing microRNA-126-3p (miR-126-3p), and hence induce SMC turnover, and that the application of atheroprotective laminar shear (LS) at 12 dynes/cm 2 to ECs inhibits this paracrine effect (3). Although extracellular microRNAs (miRNAs) have been shown to convey messages from donor cells to recipient cells, how fluid shear stress regulates endothelial miRNA secretion remains to be elucidated.Emerging evidence has suggested that extracellular miRNAs can serve as not only pu...

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Into rather unexplored terrain—transcellular transport across the blood–brain barrier

Bock

Haver

Vandenbroucke

et al. 2016

Glia

127

100

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Efficient neuronal signaling in the central nervous system strictly depends on a well-balanced microenvironment around glial cells, synapses, and axons. Unique features of the blood-brain barrier (BBB) endothelium largely determine the composition of this micro-milieu and are dependent on the tight interplay with surrounding astrocytes and pericytes. BBB endothelial cells are endowed with a highly restrictive junctional complex that occludes the intercellular cleft, thereby preventing paracellular diffusion. The paracellular pathway is subject to extensive research as integrity loss of the junctional complex is associated with many neuropathologies, inflammation, and edema. Another important feature of the BBB endothelium is the low prevalence of nonspecific, transcytotic events, including (macro)pinocytosis, clathrin-dependent and caveolin-dependent endocytosis and the subsequent trafficking of vesicles to the opposite membrane. Although less studied, evidence is accruing that this pathway importantly contributes to increased BBB permeability, often when the junctional complex remains intact. Here, we review current knowledge on the contribution of the transcellular pathway to the BBB leak observed in different pathologic conditions. In addition, we hypothesize that nonselective, large pore connexin and pannexin channels may contribute to transcellular transport, either by providing a direct diffusion pathway across the endothelial monolayer, or indirectly, by exerting control over intracellular levels of the signaling ion Ca(2+) that is involved in many steps of the vesicular pathway. We conclude that transcytotic events at the BBB, despite being less acknowledged, cannot be simply dismissed as done in the past, but actively contribute to BBB leakage in many different pathologies. GLIA 2016;64:1097-1123.

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Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

Cited by 73 publications

References 88 publications

Syntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and platelets

Syntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and platelets

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Into rather unexplored terrain—transcellular transport across the blood–brain barrier

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