ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters

Huang, Royston-Luke; Teo, Ziqiang; Chong, Han Chung; Zhu, Pengcheng; Tan, Ming; Tan, Chee Leong; Lam, Chee Ren Ivan; Sng, Ming Keat; Leong, David Tai; Tan, Soon Keat; Kersten, Sander; Ding, Jeak Ling; Hy, Li; Tan, Nguan Soon

doi:10.1182/blood-2011-01-328716

Cited by 225 publications

(244 citation statements)

References 35 publications

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“…(Fig. 5a) reduced the chance of damaging the blood vessels solely due to injection 4 . We then injected Evan's blue dye (EBD) into the tail vein and sacrificed the animals.…”

Section: Resultsmentioning

confidence: 95%

“…S1) binds directly to VE-cadherin, it can either bind directly to the extracellular domains where homophilic interaction occurs 29 and disrupts that interaction, or the other domains of VE-cadherin not involved in the homophilic interaction or even the Ca 2 þ ions itself. EDTA disrupts homophilically interacting VE-cadherin by chelating Ca 2 þ ions 4 . That may provide clues that negatively Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Endothelial cells line blood vessels in many highly vascularized organs and function as gatekeepers for nutrients, waste and cell movement. The subtle control of blood vessel integrity is so important that its dysfunction is implicated in tumour angiogenesis and metastatic migration 3,4 . Much of this control occurs right at the adherens junctions between endothelial cells.…”

mentioning

confidence: 99%

“…When this junctional continuity is disrupted, the space between adjacent endothelial cells increases to at least 1-2 mm, resulting in endothelial cell leakiness (ECL) or in an in vivo setting, vascular leakiness 3 . Species like vascular endothelial growth factor (VEGF), thrombin, angiopoietin-like 4 protein 4 and histamine 5 can perturb this tightly regulated intercellular and intracellular homeostasis and result in ECL. Toxic metal oxide NM are known to be endocytosed and induced oxidative stress 6,7 ; indirectly leading to ECL 8 .…”

mentioning

confidence: 99%

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Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE–cadherin

et al. 2013

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The use of nanomaterials has raised safety concerns, as their small size facilitates accumulation in and interaction with biological tissues. Here we show that exposure of endothelial cells to TiO 2 nanomaterials causes endothelial cell leakiness. This effect is caused by the physical interaction between TiO 2 nanomaterials and endothelial cells' adherens junction protein VE-cadherin. As a result, VE-cadherin is phosphorylated at intracellular residues (Y658 and Y731), and the interaction between VE-cadherin and p120 as well as b-catenin is lost. The resulting signalling cascade promotes actin remodelling, as well as internalization and degradation of VE-cadherin. We show that injections of TiO 2 nanomaterials cause leakiness of subcutaneous blood vessels in mice and, in a melanoma-lung metastasis mouse model, increase the number of pulmonary metastases. Our findings uncover a novel non-receptor-mediated mechanism by which nanomaterials trigger intracellular signalling cascades via specific interaction with VE-cadherin, resulting in nanomaterial-induced endothelial cell leakiness.

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“…(Fig. 5a) reduced the chance of damaging the blood vessels solely due to injection 4 . We then injected Evan's blue dye (EBD) into the tail vein and sacrificed the animals.…”

Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE–cadherin

et al. 2013

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“…36) and matrix metalloproteinases 37 , which were previously implicated in tumour-mediated disruption of endothelium integrity. Notably, angiopoietin-like 4, a matricellular protein endowing breast tumours with the capacity to disrupt lung capillaries and seed pulmonary metastases 35,38 , was absent from our proteomic analysis. In line with this, angiopoietin-like 4 was reported to prevent metastasis of melanoma B16 cells by inhibiting vascular permeability and tumour cell motility 39 .…”

Section: Discussionmentioning

confidence: 99%

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis

et al. 2015

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Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.

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Angiopoietin‐like protein 4 and clinical outcomes in ischemic stroke patients

Zheng

Shen

Wang

et al. 2021

Ann Clin Transl Neurol

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Aims Angiopoietin‐like protein 4 (ANGPTL‐4) had been reported to be associated with the risk of ischemic stroke, but its prognostic value remained unclear. The aim of this study was to investigate the association between plasma ANGPTL‐4 concentrations and prognosis of ischemic stroke. Methods Baseline plasma ANGPTL‐4 concentrations were measured in 3379 acute ischemic stroke patients. The primary outcome was a combination of death or major disability (modified Rankin Scale score, ≥3) at 3 months after ischemic stroke. Results At 3 months after ischemic stroke, 850 (26.16%) participants experienced major disability or died (750 major disabilities and 100 deaths). After adjusting for important covariates, odds ratios for the highest tertile of plasma ANGPTL‐4 concentrations were 1.59 (1.22–2.06) for primary outcome, 1.53 (1.18–1.97) for major disability, and 2.03 (1.03–4.00) for death when compared with the lowest tertile of plasma ANGPTL‐4 concentrations. For 1‐SD increase in log‐ANGPTL‐4 concentrations (0.44 ng/mL), the adjusted odds ratios were 1.24 (1.11–1.38), 1.14 (1.03–1.27), and 1.72 (1.32–2.23), respectively. Adding ANGPTL‐4 to a model containing conventional risk factors improved risk prediction for composite outcome of death and major disability. Conclusion Higher plasma ANGPTL‐4 concentration was associated with poor prognosis in acute ischemic stroke patients, suggesting that ANGPTL‐4 might be a prognostic marker for ischemic stroke.

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ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters

Cited by 225 publications

References 35 publications

Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE–cadherin

Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE–cadherin

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis

Angiopoietin‐like protein 4 and clinical outcomes in ischemic stroke patients

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