Investigating Cell-Specific Sphingosine-1-Phosphate Receptor 3 Signaling in Neurovascular Unit Dysfunction Following Ischemia

• Applicant: Professorin Dr. Anja Meissner
• Subject Area: Anatomy and Physiology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557568267

Brain injury following ischemic stroke is characterized by a deadly cycle of cerebrovascular alterations, an impairment of important neurovascular unit (NVU) and blood-brain barrier (BBB) functions and inflammation, resulting in pronounced neurodegeneration. Due to many unknowns within this complexity, treatment options are sparse. Urgently needed new advancements in this area necessitate a better mechanistic understanding of ischemia-related NVU and BBB alterations. Signaling of the bioactive phospholipid S1P has gained increasing attention in cardiovascular disease research, due to its involvement in both vascular function and immune system responses. Specifically, the modulation of S1P receptors (S1Pr) has also shown beneficial effects on cerebrovascular function and CBF in experimental models of stroke. With respect to NVU alterations, stroke-related S1Pr3 up-regulation has been found primarily in astrocytes, which confirms in vitro investigations demonstrating S1Pr3 predominance in this cell type critical to NVU functionality. Own preliminary data revealed a critical temporal involvement of astrocyte- and endothelial cell-specific S1Pr3 expression patterns with a pronounced astrocytic S1Pr3 up-regulation acutely post-stroke. To what extent S1P-S1Pr3 signaling is involved in astrocyte shapeshifting and endothelial cell responses to ischemia, and how dysregulation of this signaling axis affects communication within the NVU is still unknown. With this project, we will investigate the exact temporal contribution of cell specific S1Pr3 signaling to NVU impairment by using murine stroke models and appropriate in vitro systems that better resemble in vivo phenotypes of astrocytes and endothelial cells.

• DFG Programme: Research Grants