Vascular Signal Transducer and Activator of Transcription-3 Promotes Angiogenesis and Neuroplasticity Long-Term After Stroke

Abstract

Background-Poststroke angiogenesis contributes to long-term recovery after stroke. Signal transducer and activator of transcription-3 (Stat3) is a key regulator for various inflammatory signals and angiogenesis. It was the aim of this study to determine its function in poststroke outcome. Methods and Results-We generated a tamoxifen-inducible and endothelial-specific Stat3 knockout mouse model by crossbreeding Stat3 floxed/KO and Tie2-Cre ERT2 mice. Cerebral ischemia was induced by 30 minutes of middle cerebral artery occlusion. We demonstrated that endothelial Stat3 ablation did not alter lesion size 2 days after ischemia but did worsen functional outcome at 14 days and increase lesion size at 28 days. At this late time point vascular Stat3 expression and phosphorylation were still increased in wild-type mice. Gene array analysis of a CD31-enriched cell population of the neurovascular niche showed that endothelial Stat3 ablation led to a shift toward an antiangiogenic and axon growthinhibiting micromilieu after stroke, with an increased expression of Adamts9. Remodeling and glycosylation of the extracellular matrix and microglia proliferation were increased, whereas angiogenesis was reduced. Conclusions-Endothelial

Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice

“…The JAK2/STAT3 signaling pathway is involved in cell proliferation, cell-cycle progression, and angiogenesis, and it is associated with antiphospholipid antibodies-mediated inhibition of endometrial angiogenesis and leptin-induced neovascularization in diabetic retinopathy (Darnell et al 1994;Suganami et al 2004;D'Ippolito et al 2012;Raible et al 2014). Especially, increasing evidence has shown that the JAK2/STAT3 signaling pathway plays a primary role in stroke induced angiogenesis (Sakata et al 2012;Hoffmann et al 2015). Thus, we investigated the role of the JAK2/ STAT3 signaling pathway in Sals-induced post-stroke angiogenesis.…”

“…; Hoffmann et al . ). However, an outstanding question is that angiogenic vessels are permeable, so that maturation of the vessel walls is necessary to ensure a stable vascular system, and the coverage of endothelium by pericytes and astrocytic endfeet delivers (at least partly) the solution (Rigau et al .…”

“…; Hoffmann et al . ). STAT3 is phosphorylated by phospho‐Janus kinase 2 (pJAK2) and subsequently translocated into the cell nucleus, where it regulates the expression of target genes (Liu et al .…”

“…Vascular endothelial growth factor (VEGF), a crucial stimulator for blood vessel formation, initiates formation of immature vessels, and angiopoietins (Angs) are involved in maturation, stabilization, and remodeling of the initially immature vasculature (Yancopoulos et al 2000). As a direct transcriptional activator of VEGF under hypoxia, signal transducer and activator of transcription 3 (STAT3) has recently been shown to promote post-stroke angiogenesis (Gertz et al 2012;Hoffmann et al 2015). STAT3 is phosphorylated by phospho-Janus kinase 2 (pJAK2) and subsequently translocated into the cell nucleus, where it regulates the expression of target genes (Liu et al 2014b;Quarta et al 2014).…”

Calmodulin‐like skin protein protects against spatial learning impairment in a mouse model of Alzheimer disease

“…Recently, it was reported that the activation of the JAK/STAT3 pathway promotes synapse formation and axon outgrowth in the injured brain (Hoffmann et al . ; Chen et al . ).…”