An S1P1 agonist, ASP4058, suppresses intracranial aneurysm through promoting endothelial integrity and blocking macrophage transmigration.

BACKGROUND AND PURPOSE Intracranial aneurysm (IA), common in general public, causes lethal subarachnoid hemorrhage on rupture. Prevention of rupture of IA is therefore socially important. However, there is currently no medical treatment. Recent studies suggest that IA is a disease of chronic inflammation in the arterial wall caused by endothelial dysfunction and infiltrated macrophages. Sphingosine-1-phosphate receptor type 1 (S1P1) is present on the endothelium and promotes its barrier function. Here we have tested the potential of an S1P1 agonist, ASP4058, in prevention of IA in animal model. EXPERIMENTAL APPROACH A selective S1P1 agonist, ASP4058, was used. Its effects on endothelial permeability and migration of macrophages across endothelial cell monolayer were tested in vitro using a Transwell system, and effects of ASP4058 on size of IAs induced in a rat model was evaluated in rat IA model. KEY RESULTS S1P1 receptor was expressed in endothelial cells of human IA lesions and control arterial walls. ASP4058 significantly reduced FITC-dextran leakage through endothelial monolayer and suppressed migration of macrophages across the monolayer in vitro. Oral administration of ASP4058 suppressed vascular permeability, macrophage infiltration and size of IAs by acting as an S1P1 agonist in rat model. This effect was mimicked by two other structurally-unrelated S1P1 agonists. CONCLUSION AND IMPLICATIONS A selective S1P1 agonist is a strong drug candidate for IA treatment through promoting endothelial cell barrier and suppressing trans-endothelial migration of macrophages in IA lesions. Non-approved abbreviations anterior cerebral artery, ACA; 3-aminopropionitrile, BAPN; Chinese hamster ovary, CHO; diastolic blood pressures, DBP; geometric mean fluorescence intensity, geoMFI; human carotid artery endothelial cells, HCtAEC; Intracranial aneurysm, IA; mean blood pressures, MBP; methylcellulose, MC; olfactory artery, OA; α-smooth muscle actin, SMA; systolic blood pressures, SBP; Sphigosine-1-phosphate, S1P; Transmission Electron Microscopy, TEM; wall shear stress, WSS