Stromal cell–derived factor-1 promoted angiogenesis and inflammatory cell infiltration in aneurysm walls

Abstract

Object A small percentage of cerebral aneurysms rupture, but when they do, the effects are devastating. Current management of unruptured aneurysms consist of surgery, endovascular treatment, or watchful waiting. If the biology of how aneurysms grow and rupture were better known, a novel drug could be developed to prevent unruptured aneurysms from rupturing. Ruptured cerebral aneurysms are characterized by inflammation-mediated wall remodeling. We studied the role of stromal cell-derived factor-1 (SDF-1) in inflammation-mediated wall remodeling in cerebral aneurysms. Methods Human aneurysms; murine carotid aneurysms; and murine intracranial aneurysms were studied by immunohistochemistry. Flow cytometry analysis was performed on blood from mice developing carotid aneurysms or intracranial aneurysms. The effect of SDF-1 on endothelial cells and macrophages was studied by chemotaxis cell migration assay and capillary tube formation assay. Anti-SDF-1 blocking antibody was given to mice and compared to control (vehicle)-administered mice for its effects on the walls of carotid aneurysms and the development of intracranial aneurysms. Results Human aneurysms, murine carotid aneurysms, and murine intracranial aneurysms, all express SDF-1; and mice with developing carotid aneurysms or intracranial aneurysms have increased progenitor cells expressing CXCR4, the receptor for SDF-1 (P<0.01 and P<0.001, respectively). Human aneurysms and murine carotid aneurysms have endothelial cells, macrophages, and capillaries in the walls of the aneurysms; and the presence of capillaries in the walls of human aneurysms is associated with presence of macrophages (P=0.01). SDF-1 promotes endothelial cell and macrophage migration (P<0.01 for each), and promotes capillary tube formation (P<0.001). When mice are given anti-SDF-1 blocking antibody, there is a significant reduction in endothelial cells (P<0.05), capillaries (P<0.05), and cell proliferation (P<0.05) in the aneurysm wall. Mice given anti-SDF-1 blocking antibody develop significantly fewer intracranial aneurysms (33% versus 89% in mice given control IgG)(P<0.05). Conclusions These data suggest SDF-1 associated with angiogenesis and inflammatory cell migration and proliferation in the walls of aneurysms, and may have a role in the development of intracranial aneurysms.

Diagnostic limitations in the treatment of cerebral aneurysms

“…In various studies, it could be demonstrated, that aneurysm rupture and growth are mediated by angiogenesis, infl ammatory cell infi ltration (23,24) or extracellular matrix degeneration (25) in the aneurysmal wall. Further, immunohistochemical analyses revealed differences in structural protein and vascular growth factor expressions in normal artery, as well as unruptured and ruptured aneurysm walls (26).…”

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…Study findings also showed SDF-1 to promote endothelial cell migration, endothelial cell tube formation (angiogenesis), and macrophage migration. [16] Inhibition of SDF-1 in the murine model significantly decreased the amount of endothelial cells and capillaries in the aneurysm wall, and the overall rate of aneurysm formation was reduced. [16] …”

“…[16] Inhibition of SDF-1 in the murine model significantly decreased the amount of endothelial cells and capillaries in the aneurysm wall, and the overall rate of aneurysm formation was reduced. [16] …”

“…[15] As cerebral vessel walls undergo change during aneurysm development, the formation of new vessels, angiogenesis, also contributes to aneurysmal progression. [16] Angiogenesis indirectly advances the inflammatory process of aneurysm progression by aiding in the delivery of inflammatory cells to vessel walls. Hoh et al [16] recently showed that stromal cell-derived factor-1 (SDF-1) is expressed in murine carotid IAs, murine circle of Willis IAs, and human cerebral aneurysms.…”

“…[16] Angiogenesis indirectly advances the inflammatory process of aneurysm progression by aiding in the delivery of inflammatory cells to vessel walls. Hoh et al [16] recently showed that stromal cell-derived factor-1 (SDF-1) is expressed in murine carotid IAs, murine circle of Willis IAs, and human cerebral aneurysms. The study found increased levels of progenitor cells expressing the SDF-1 receptor, CXCR4, in mice with carotid and cerebral aneurysms.…”