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Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice
Ri Yu1,2, Nam-Suk Kim1, Yan Li1
1Neurovascular Biology Laboratory, Neurovascular Unit Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
Translational Stroke Research
|May 12, 2021
Summary
Semaphorin 3E (Sema3E)-Plexin-D1 signaling promotes brain recovery after stroke by regulating blood vessel repair and blood-brain barrier integrity. This pathway downregulates vascular endothelial growth factor (VEGF) signaling, improving neurological function and reducing infarct size.
Area of Science:
- Neuroscience
- Vascular Biology
- Regenerative Medicine
Background:
- Post-stroke functional recovery depends on cerebrovascular remodeling, including angiogenesis.
- Mechanisms coordinating vascular repair pathways after ischemic injury are not fully understood.
- Axon guidance molecules, like Semaphorin 3E (Sema3E) and its receptor Plexin-D1, are emerging as critical regulators of vascular remodeling.
Purpose of the Study:
- To investigate the role of Sema3E-Plexin-D1 signaling in cerebrovascular remodeling following ischemic stroke.
- To determine the impact of this signaling pathway on functional recovery, blood-brain barrier integrity, and vascular morphogenesis after stroke.
Main Methods:
- Utilized a mouse model of transient brain infarction.
- Analyzed Sema3e and Plexin-D1 expression in response to ischemic injury.
- Assessed neurological deficits, infarct volume, neuronal survival, and blood flow recovery in wild-type and Plxnd1 knockout mice.
- Evaluated blood-brain barrier integrity using tracer extravasation and junctional protein analysis.
- Investigated the effect of VEGF signaling inhibition in Plxnd1 knockout mice.
Main Results:
- Ischemic injury induced rapid Sema3e expression and subsequent Plexin-D1 upregulation in remodeling brain vessels.
- Plxnd1 ablation exacerbated neurological deficits, increased infarct volume, reduced neuronal survival, and impaired blood flow recovery.
- Absence of Sema3E-Plexin-D1 signaling led to blood-brain barrier breakdown, characterized by tracer extravasation and altered junctional proteins.
- Inhibition of vascular endothelial growth factor (VEGF) signaling restored vascular phenotype and BBB integrity in Plxnd1 knockout mice.
Conclusions:
- Sema3E-Plexin-D1 signaling is crucial for effective cerebrovascular remodeling and functional recovery after ischemic stroke.
- This pathway promotes recovery by downregulating aberrant VEGF signaling, thereby maintaining blood-brain barrier integrity and supporting proper vascular morphogenesis.
- Targeting the Sema3E-Plexin-D1 pathway offers a potential therapeutic strategy for stroke recovery.
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