Mast Cell Promotes the Development of Intracranial Aneurysm Rupture

Stroke. 2020 Nov;51(11):3332-3339. doi: 10.1161/STROKEAHA.120.030834. Epub 2020 Oct 6.

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 (KitW-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 KitW-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneurysm, Ruptured / immunology*
  • Aneurysm, Ruptured / pathology
  • Aneurysm, Ruptured / prevention & control
  • Animals
  • Cathepsin G / genetics
  • Chymases / genetics
  • Cromolyn Sodium / pharmacology
  • Disease Models, Animal
  • Interleukin-6 / genetics
  • Intracranial Aneurysm / immunology*
  • Intracranial Aneurysm / pathology
  • Male
  • Mast Cell Stabilizers / pharmacology
  • Mast Cells / drug effects
  • Mast Cells / immunology*
  • Mast Cells / pathology
  • Matrix Metalloproteinase 9 / genetics
  • Mice
  • Mice, Transgenic
  • Mutation
  • Proto-Oncogene Proteins c-kit / genetics
  • RNA, Messenger / metabolism
  • Receptor, Angiotensin, Type 1 / genetics
  • Subarachnoid Hemorrhage / immunology
  • Subarachnoid Hemorrhage / pathology
  • Subarachnoid Hemorrhage / prevention & control
  • Tryptases / genetics
  • Tumor Necrosis Factor-alpha / genetics
  • p-Methoxy-N-methylphenethylamine / pharmacology

Substances

  • Interleukin-6
  • Mast Cell Stabilizers
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Tnf protein, mouse
  • Tumor Necrosis Factor-alpha
  • interleukin-6, mouse
  • p-Methoxy-N-methylphenethylamine
  • Proto-Oncogene Proteins c-kit
  • Cathepsin G
  • Ctsg protein, mouse
  • Chymases
  • Tryptases
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • Cromolyn Sodium