Phospholipases in Health and Disease

Yang, Yong Ryoul; Jang, Hyun‐Jun; Ryu, Sung Ho; Suh, Pann‐Ghill

doi:10.1007/978-1-4939-0464-8_1

Cited by 5 publications

(5 citation statements)

References 217 publications

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“…As well as direct and indirect effects of DAG at the plasma membrane resulting in extracellular calcium entry into the cell as well as other signaling events. 25,26,42–44 In order to assess events upstream of the observed differences in VEGFA-induced calcium flux, the cellular levels of PIP2 were evaluated in shTIME cells under basal and VEGFA-stimulated conditions.…”

Section: Resultsmentioning

confidence: 99%

“…Known activators of PLC include Ca 2+ , heterotrimeric G proteins, small G proteins, and receptor/non-receptor tyrosine kinases. 25,26 PLC isozymes are responsible for a wide array of physiological functions. Regarding the role of PLC isozymes in the regulation of vascular function, PLCγ1 regulates VEGFA-mediated endothelial cell migration, positively controls vascular permeability induced by VEGFA, and plays a key role in arterial development.…”

Section: Nonstandard Abbreviations and Acronymsmentioning

confidence: 99%

“…As well as direct and indirect effects of DAG at the plasma membrane resulting in extracellular calcium entry into the cell as well as other signaling events. 25,26,[42][43][44] In order to assess events upstream of the observed differences in VEGFA-induced calcium flux, the cellular levels of PIP2 were evaluated in shTIME cells under basal and VEGFA-stimulated conditions. To determine whether these mechanisms of control by PLCβ2 in microvascular permeability would provide any benefit under pathological conditions, two disease models with a vascular permeability component were evaluated in WT and PLCβ2-null mice as a validation of the observed dermal vascular permeability response.…”

Section: Plcβ2 Regulates Pip2 Levels In Endothelial Cellsmentioning

confidence: 99%

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Phospholipase Cβ2 Promotes Vascular Endothelial Growth Factor Induced Vascular Permeability

Phoenix

Yue

et al. 2022

Preprint

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Background: Regulation of vascular permeability (VP) is critical to maintaining tissue metabolic homeostasis. Vascular endothelial growth factor (VEGF) is a key stimulus of VP in acute and chronic diseases including ischemia reperfusion injury, sepsis and cancer. Identification of novel regulators of VP would allow for the development of effective targeted therapeutics for patients with unmet medical need. Methods: In vitro and in vivo models of VEGFA-induced vascular permeability, pathological permeability, quantitation of intracellular calcium release and cell entry, and PIP2 levels were evaluated with and without modulation of PLCβ2. Results: Global knock-out of PLCβ2 in mice resulted in blockade of VEGFA-induced vascular permeability in vivo and trans-endothelial permeability in primary lung endothelial cells. Further work in an immortalized human microvascular cell line modulated with stable knock-down of PLCβ2 recapitulated the observations in the mouse model and primary cell assays. Additionally, loss of PLCβ2 limited both intracellular release and extracellular entry of calcium following VEGF stimulation as well as reduced basal and VEGFA-stimulated levels of PIP2 compared to control cells. Finally, loss of PLCβ2 in both a hyperoxia induced lung permeability model and a cardiac ischemia:reperfusion model resulted in improved animal outcomes when compared to WT controls. Conclusions: The results implicate PLCβ2 as a key positive regulator of VEGF-induced VP through regulation of both calcium flux and PIP2 levels at the cellular level. Targeting of PLCβ2 in a therapeutic setting may provide a novel approach to regulating vascular permeability in patients.

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Section: Resultsmentioning

confidence: 99%

Section: Nonstandard Abbreviations and Acronymsmentioning

confidence: 99%

Section: Plcβ2 Regulates Pip2 Levels In Endothelial Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Phospholipase Cβ2 Promotes Vascular Endothelial Growth Factor Induced Vascular Permeability

Phoenix

Yue

et al. 2022

Preprint

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“…These events result in changes in cytoplasmic calcium flux through inositol 1,4,5-trisphosphate-induced calcium release of intracellular calcium from endoplasmic reticulum, as well as direct and indirect effects of diacylglycerol at the plasma membrane resulting in extracellular calcium entry into the cell as well as other signaling events. 25,26,[43][44][45] To assess events upstream of the observed differences in VEGFA-induced calcium flux, the cellular levels of PIP2 were evaluated in shTIME cells under basal and VEGFA-stimulated conditions.…”

Section: Plcβ2 Regulates Pip2 Levels In Endothelial Cellsmentioning

confidence: 99%

“…Known activators of PLC include Ca 2+ , heterotrimeric G proteins, small G proteins, and receptor/nonreceptor tyrosine kinases. 25,26 PLC isozymes are responsible for a wide array of physiological functions. Regarding the role of PLC isozymes in the regulation of vascular function, PLCγ1 regulates VEGFA-mediated endothelial cell migration, positively controls VP induced by VEGFA, and plays a key role in arterial development.…”

mentioning

confidence: 99%

PLCβ2 Promotes VEGF-Induced Vascular Permeability

Phoenix

Yue

et al. 2022

ATVB

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Background: Regulation of vascular permeability is critical to maintaining tissue metabolic homeostasis. VEGF (vascular endothelial growth factor) is a key stimulus of vascular permeability in acute and chronic diseases including ischemia reperfusion injury, sepsis, and cancer. Identification of novel regulators of vascular permeability would allow for the development of effective targeted therapeutics for patients with unmet medical need. Methods: In vitro and in vivo models of VEGFA-induced vascular permeability, pathological permeability, quantitation of intracellular calcium release and cell entry, and phosphatidylinositol 4,5-bisphosphate levels were evaluated with and without modulation of PLC (phospholipase C) β2. Results: Global knock-out of PLCβ2 in mice resulted in blockade of VEGFA-induced vascular permeability in vivo and transendothelial permeability in primary lung endothelial cells. Further work in an immortalized human microvascular cell line modulated with stable knockdown of PLCβ2 recapitulated the observations in the mouse model and primary cell assays. Additionally, loss of PLCβ2 limited both intracellular release and extracellular entry of calcium following VEGF stimulation as well as reduced basal and VEGFA-stimulated levels of phosphatidylinositol 4,5-bisphosphate compared to control cells. Finally, loss of PLCβ2 in both a hyperoxia-induced lung permeability model and a cardiac ischemia:reperfusion model resulted in improved animal outcomes when compared with wild-type controls. Conclusions: The results implicate PLCβ2 as a key positive regulator of VEGF-induced vascular permeability through regulation of both calcium flux and phosphatidylinositol 4,5-bisphosphate levels at the cellular level. Targeting of PLCβ2 in a therapeutic setting may provide a novel approach to regulating vascular permeability in patients.

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