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Integrin α5β1-Ang1/Tie2 Receptor Cross-talk Regulates Brain Endothelial Cell Responses Following Cerebral Ischemia

Defang Pang, Lu Wang, Jing Dong, Xiaoyin Lai, Qijuan Huang, R. Milner, Longxuan Li
Published 2018 · Chemistry, Medicine

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We have previously demonstrated that in response to cerebral ischemia (CI), the growth factor angiopoietin-1 (Ang1) and α5β1 integrin are both induced in cerebral vessels, which likely provide positive signals driving the endogenous angiogenic response and vascular protection after CI. However, the precise relationship between endothelial Ang1 and α5β1 integrin after CI remains poorly understood. Here, we investigated the effects of the interaction between the Ang1/Tie2 system and α5β1 integrin on brain endothelial cells (BECs) under cerebral ischemic conditions in vivo and in vitro. Immunofluorescence analysis demonstrated that integrin α5β1 co-localized with Tie2/phosphorylated Tie2 on cerebral vessels in the penumbra. The in vitro study showed that oxygen–glucose deprivation/restoration (OGD/R) induced the expression of the Ang1 receptor Tie2 on BECs in a manner similar to that for integrin α5 and Ang1 in response to OGD/R, accompanied by increased activation of Tie2 and its downstream effectors focal adhesion kinase (FAK) and Akt. Knockdown of α5 integrin markedly suppressed OGD/R-induced Tie2 receptor activation in BECs, while in contrast, priming BECs with Ang1 promoted the expression of α5 integrin as well as the Tie2 downstream transcription factor Ets-1 in OGD-treated BECs. In line with this, Ets-1 knockdown significantly attenuated Ang1-mediated upregulation of α5 integrin. Functionally, Ang1 induced cell migration and tube formation of BECs after OGD, but this effect was inhibited by diminishment of the levels of α5 integrin in BECs. Taken together, our data indicate that the Ang1/Tie2 system cross-talks with integrin α5β1 in BECs after CI, which may contribute to the endogenous angiogenic vascular protective response following CI.Stroke: Interacting signals promote new blood vessel formationInteractions between two molecular signaling systems on the surface of brain blood vessel cells may regulate the response to cerebral ischemic (CI) strokes, in which the blood supply and hence oxygen to part of the brain is interrupted by blockages, such as blood clots. Researchers led by Longxuan Li at Gongli Hospital, the Second Military Medical University, Shanghai, and Richard Milner at the Scripps Research Institute, La Jolla, USA, used mice and cultured cells to study these interactions. The results suggest that the cell surface receptor proteins that mediate both signaling systems localize in the same area of blood cell membranes in response to a CI stroke. Molecular “cross-talk” between these systems may promote the formation of new blood vessels to repair the damage caused by a stroke. These insights could assist development of drugs to treat CI strokes.
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Taishan People's Hospital, Taishan 529200, P. R. China. 6 Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road
2 Department of Neurology, Gongli Hospital, The Second Military Medical University
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