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Mass-spectrometry analysis of isolated brain vessels from vehicle treated Foxf2iECKO, vehicle-treated Ctrl, and AKB-9778 treated Foxf2iECKO mice

ABSTRACT: To further characterize the role of endothelial Foxf2 in the maintenance of vascular function and examine a possible mediating effect of Tie2 signaling, we pharmacologically modulated Tie2 activity in mice and performed subsequent in vivo analyses together with studies on isolated brain vessels. Specifically, we applied AKB-9778, a selective small molecule inhibitor of vascular endothelial protein tyrosine phosphatase (Ptprb, VE-PTP) previously shown to stabilize the vasculature through Tie2 activation (Saharinen, et al., 2016; Shen et al., 2014). Mass-spectrometry analysis of isolated brain vessels from vehicle-treated Foxf2iECKO and Ctrl mice (Foxf2iECKO-Veh and Ctrl-Veh, respectively) confirmed the dysregulation of multiple proteins related to Tie2 signaling. Treatment with AKB-9778 for 48h restored their levels. Specifically, the abundance of Nos3, Nostrin and Gucy1b1 (implicated in nitric oxide metabolic process), Cldn5, Ctnnd1, Pecam1, and Rap1b (implicated in establishment of endothelial barrier), and Tie2, Flt1, and Itgb1 (implicated in angiogenesis) were all upregulated upon Tie2 activation. Collectively, these findings demonstrate that AKB-9778 rescues the deficiency of Tie2 signaling in mouse BECs lacking Foxf2.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Microvessel

DISEASE(S): Brain Small Vessel Disease

SUBMITTER: Stephan Mueller

LAB HEAD: Stefan F.

PROVIDER: PXD051839 | Pride | 2025-09-02

REPOSITORIES: Pride

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			Action	DRS
	KO_1_Slot2-3_1_4010.d.zip	Other
	KO_3_Slot2-7_1_4014.d.zip	Other
	KO_4_Slot2-13_1_4024.d.zip	Other
	KO_5_Slot2-15_1_4030.d.zip	Other
	RAZ_1_Slot2-10_1_4021.d.zip	Other

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Mass-spectrometry analysis of vehicle or AKB-9778 treated FOXF2KO and WT human endothelial cells

Project description:To validate our results on Foxf2 related Tie2 signaling and explore their transferability to human cells, we studied human iPSC-derived endothelial cells (iECs). FOXF2KO and WT iECs (González-Gallego et al., in preparation) were treated with AKB-9778 or vehicle and assessed by proteomics. Similar to our results in mouse BECs, proteomic analysis revealed a dysregulation of multiple members of the TIE2 signaling pathway in vehicle treated FOXF2KO compared to WT iECs including TIE2 and NOS3. Moreover, treatment with AKB-9778 restored the levels of multiple TIE2 signaling related proteins. Collectively, these findings demonstrate that AKB-9778 rescues the deficiency of TIE2 signaling in human endothelial cells lacking FOXF2. González-Gallego, J. et al. A fully iPSC-derived 3D model of the human blood-brain-barrier for exploring neurovascular disease mechanisms and therapeutic interventions - in preparation, available from editorial office upon request.

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