Mast Cell Promotes the Development of Intracranial Aneurysm Rupture

Abstract

Background and purpose: Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture.

Methods: Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (Kit^W-sh/W-sh mice).

Results: Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus Kit^W-sh/W-sh mice).

Conclusions: These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.

Keywords: intracranial aneurysm; mast cells; mice; subarachnoid hemorrhage; tryptase.

Figure 1.. Presence of mast cells in mouse intracranial aneurysms.

Representative images of immunohistochemical staining of mast cells in mouse intracranial aneurysms. Brown color indicates positive staining for mast cells. Arrows indicate mast cells. “X” indicates the lumen of aneurysms. Scale bar: 50 μm.

Figure 2.. Pharmacological stabilization of mast cells by cromolyn after aneurysm formation prevented aneurysmal rupture,

A. Time window of the mast cell stabilization treatment by cromolyn. B. No difference in the incidence of aneurysm between cromolyn-treated and vehicle-treated mice. C. Aneurysm rupture rate was significantly decreased in cromolyn-treated as compared to vehicle-treated mice. * P < 0.05.

Figure 3.. The mast cell stabilization during aneurysmal formation did not affect aneurysm rupture.

A. Time window of the mast cell stabilization treatment by cromolyn. B, C. No difference in the incidence of aneurysms or rupture rate was found between cromolyn-treated and vehicle-treated mice.

Figure 4.. Pharmacological activation of mast cells after aneurysm formation promoted aneurysmal rupture without affecting the aneurysmal formation.

A. Time window of the mast cell activation treatment by C48/80. B. No difference in the incidence of aneurysm between C48/80-treated and vehicle-treated mice. C. Aneurysm rupture rate was significantly increased in C48/80-treated as compared to vehicle-treated mice. * P < 0.05.

Figure 5.. Genetic deficiency of mast cells decreased the aneurysmal rupture rate without affecting the aneurysmal formation.

A. No difference in the incidence of aneurysm between the Kit^W-sh/W-sh mice and the wild-type mice. B. Aneurysm rupture rate was significantly decreased in the Kit^W-sh/W-sh mice as compared to the wild-type mice. * P < 0.05.

Figure 6.. Genetic deficiency of mast cells eliminated cromolyn treatment effects.

A. Time window of the mast cell stabilization treatment by cromolyn in the Kit^W-sh/W-sh mice. B, C. No difference in the incidence of aneurysm or rupture rate was found between cromolyn-treated and vehicle-treated groups in the Kit^W-sh/W-sh mice.