Critical roles of macrophages in the formation of intracranial aneurysm.
OBJECTIVE
abnormal vascular remodeling triggered by hemodynamic stresses and inflammation is believed to be a key process in the pathophysiology of intracranial aneurysms. Numerous studies have shown infiltration of inflammatory cells, especially macrophages, into intracranial aneurysmal walls in humans. Using a mouse model of intracranial aneurysms, we tested whether macrophages play critical roles in the formation of intracranial aneurysms.


METHODS
intracranial aneurysms were induced in adult male mice using a combination of a single injection of elastase into the cerebrospinal fluid and angiotensin II-induced hypertension. Aneurysm formation was assessed 3 weeks later. Roles of macrophages were assessed using clodronate liposome-induced macrophage depletion. In addition, the incidence of aneurysms was assessed in mice lacking monocyte chemotactic protein-1 (CCL2) and mice lacking matrix metalloproteinase-12 (macrophage elastase).


RESULTS
intracranial aneurysms in this model showed leukocyte infiltration into the aneurysmal wall, the majority of the leukocytes being macrophages. Mice with macrophage depletion had a significantly reduced incidence of aneurysms compared with control mice (1 of 10 versus 6 of 10; P<0.05). Similarly, there was a reduced incidence of aneurysms in mice lacking monocyte chemotactic protein-1 compared with the incidence of aneurysms in wild-type mice (2 of 10 versus 14 of 20, P<0.05). There was no difference in the incidence of aneurysms between mice lacking matrix metalloproteinase-12 and wild-type mice.


CONCLUSIONS
these data suggest critical roles of macrophages and proper macrophage functions in the formation of intracranial aneurysms in this model.
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA. hashimot@anesthesia.ucsf.edu
Yasuhisa
Y
Kanematsu
Miyuki
M
Kanematsu
Chie
C
Kurihara
Yoshiteru
Y
Tada
Tsung-Ling
TL
Tsou
Nico
N
van Rooijen
Michael T
MT
Lawton
William L
WL
Young
Elena I
EI
Liang
Yoshitsugu
Y
Nuki
Tomoki
T
Hashimoto
D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010196:Pancreatic Elastase / Q000009:adverse effects / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000009:adverse effects / Q000494:pharmacology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010196:Pancreatic Elastase; D053508:Matrix Metalloproteinase 12