A sphingosine‐1‐phosphate receptor type 1 agonist, ASP4058, suppresses intracranial aneurysm through promoting endothelial integrity and blocking macrophage transmigration

Abstract

Background and PurposeIntracranial aneurysm (IA), common in the general public, causes lethal subarachnoid haemorrhage on rupture. It is, therefore, of utmost importance to prevent the IA from rupturing. However, there is currently no medical treatment. Recent studies suggest that IA is the result of chronic inflammation in the arterial wall caused by endothelial dysfunction and infiltrating macrophages. The sphingosine‐1‐phosphate receptor type 1 (S1P1 receptor) is present on the endothelium and promotes its barrier function. Here we have tested the potential of an S1P1 agonist, ASP4058, to prevent IA in an animal model.Experimental ApproachThe effects of a selective S1P1 agonist, ASP4058, on endothelial permeability and migration of macrophages across an endothelial cell monolayer were tested in vitro using a Transwell system, and its effects on the size of IAs were evaluated in a rat model of IA.Key ResultsS1P1 receptor was expressed in endothelial cells of human IA lesions and control arterial walls. ASP4058 significantly reduced FITC‐dextran leakage through an endothelial monolayer and suppressed the migration of macrophages across the monolayer in vitro. Oral administration of ASP4058 reduced the vascular permeability, macrophage infiltration and size of the IAs by acting as an S1P1 agonist in the rat model. This effect was mimicked by another two structurally‐unrelated S1P1 agonists.Conclusion and ImplicationsA selective S1P1 agonist is a strong drug candidate for IA treatment as it promotes the endothelial cell barrier and suppresses the trans‐endothelial migration of macrophages in IA lesions.

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“…In addition, such a factor may be applicable to develop drugs for many other macrophage-related diseases. As described in greater detail below, we have recently identified Sphingosine-1-phosphate receptor type 1 (S1P 1 ) and PGE receptor subtype 2 (EP2) as a strong therapeutic target [5,6] (Figure 1).…”

“…Recently, we have identified S1P 1 as a factor related with trans-endothelial migration of macrophages in IA lesions and proposed the potential of a selective S1P 1 agonist, ASP4058, as a candidate for treatment [6] ( Figure 1). This receptor is expressed in endothelial cells of arterial walls including IA lesions.…”

“…This receptor is expressed in endothelial cells of arterial walls including IA lesions. ASP4058 acts on endothelial cells as an agonist to reduce permeability and migration of macrophages across endothelial monolayer in in vitro system [6]. In IA lesions of rats, a part of endothelial cell junctions are dissociated and vascular permeability is increased, which can be restored by administration of ASP4058 [6].…”

“…ASP4058 acts on endothelial cells as an agonist to reduce permeability and migration of macrophages across endothelial monolayer in in vitro system [6]. In IA lesions of rats, a part of endothelial cell junctions are dissociated and vascular permeability is increased, which can be restored by administration of ASP4058 [6]. Presumably as a result of stabilization of endothelial barrier, oral administration of ASP4058 significantly suppresses macrophage infiltration and IA progression [6].…”

“…In IA lesions of rats, a part of endothelial cell junctions are dissociated and vascular permeability is increased, which can be restored by administration of ASP4058 [6]. Presumably as a result of stabilization of endothelial barrier, oral administration of ASP4058 significantly suppresses macrophage infiltration and IA progression [6]. Importantly, a non-selective S1P receptor agonist, fingolimod, fails to suppress but rather exacerbates IA progression [6], suggesting the presence of a S1P receptor oppositely functioning from S1P 1 and thus the importance of a prominent selectivity to S1P 1 over other S1P receptor subtypes.…”