Vascular Stat3 Promotes Angiogenesis and Neuroplasticity Long-Term After Stroke
Background—Post-stroke 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 post stroke outcome.
Methods and Results—We generated a tamoxifen-inducible and endothelial-specific Stat3 knockout mouse model by crossbreeding Stat3floxed/KO and Tie2-CreERT2 mice. Cerebral ischemia was induced by 30 minutes of middle cerebral artery occlusion (MCAo). 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 wildtype 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 anti-angiogenic and axon growth-inhibiting micro-milieu after stroke, with an increased expression of Adamts9. Remodeling and glycosylation of the extracellular matrix (ECM) as well as microglia proliferation were increased while angiogenesis was reduced.
Conclusions—Endothelial Stat3 regulates angiogenesis, axon growth and ECM-remodeling and is essential for long-term recovery after stroke. It might serve as a potent target for stroke treatment after the acute phase by fostering angiogenesis and neuroregeneration.
- gene microarray
- vascular niche
- chondroitin proteoglycans
- cerebral ischemia
- endothelial cell
- extracellular matrix
- Received September 5, 2014.
- Revision received March 3, 2015.
- Accepted March 13, 2015.