Phospholipase Cβ2 Promotes Vascular Endothelial Growth Factor Induced Vascular Permeability

Abstract

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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“…Macrophage-released cytokines, for example, the TGF-β, FGF, and vascular EGF (VEGF) will promote angiogenesis and modulate endothelial cell proliferation 30 . VEGF and receptors play a vital role in regulating angiogenesis and vascular permeability 31 . VEGF-A binds and activates two tyrosine kinase receptors, VEGFR (VEGF receptor)-1 and VEGFR-2, and ultimately leads to angiogenesis, which is important in tumorigenesis 32 .…”