Abstract Number: PB0103
Meeting: ISTH 2020 Congress
Background: Internalization and degradation of VE-cadherin, a major constituent of adherens junctions, lead to vascular permeability, a situation which can be dramatic in pathological situations such as ischemic stroke. This pathological context is characterized by a profound inflammatory response followed by a rupture of the blood-brain barrier with endothelial junction opening, leukocyte infiltration, edema formation and neuronal death. Therefore, the possibility to manipulate the levels of VE-cadherin at vascular adherens junctions is of potential therapeutic interest. Class II PI3KC2β is mainly thought to produce phosphatidylinositol 3-phosphate (PI3P), a phosphoinositide known to control intracellular trafficking. However, among the 3 isoforms of this class of PI3K, the function of the beta isoform (PI3KC2β) remains poorly investigated and it’s role in trafficking is poorly known.
Aims: To investigate whether PI3KC2β and its lipid product could influence VE-cadherin trafficking and endothelial permeability under the pathological conditions of ischemic stroke.
Methods: For this study we used human cerebral microvascular endothelial cells (hCMEC/D3) knock-down for PI3KC2β and PI3KC2βD1212A/D1212A kinase-dead knock-in mice and WT littermates.
Results: We showed that the knock-down of PI3KC2β in hCMEC/D3 cells increased the stability of homotypic cell-cell junctions and enhanced VE-cadherin delivery to the plasma membrane. Interestingly, PI3KC2β inactivation prevented the production of a specific pool of PI3P, resulting in a decrease in early endosomal maturation towards lysosomal degradation and an increase in endosomal recycling. In vivo, we found that genetic inactivation of PI3KC2β conferred a remarkable protection against ischemic stroke in two mouse models. Indeed, inhibition of PI3KC2β led to a stabilization of the blood-brain barrier resulting in a reduction of infarct volume, edema and inflammation.
Conclusions: These data identify the PI3KC2β as an attractive therapeutic target in ischemic stroke and reperfusion. This is of relevance to the increasing global incidence of human diseases with compromised homeostasis of the blood-brain barrier.
To cite this abstract in AMA style:Anquetil T, Solinhac R, Jaffre A, Chicanne G, Hnia K, Viaud J, Darcourt J, Orset C, Göb E, Kleinschnitz C, Vanhaesebroeck B, Vivien D, Payrastre B, Gratacap M-. PI3KC2β Deficiency Stabilizes Adherens Junctions and Preserves Vascular Integrity in Stroke Models [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/pi3kc2%ce%b2-deficiency-stabilizes-adherens-junctions-and-preserves-vascular-integrity-in-stroke-models/. Accessed January 28, 2022.
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