Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

Abstract

Aortic dissection and intramural haematoma comprise an aortopathy involving separation of the aortic wall. Underlying mechanisms of the condition remain unclear. Here we show that granulocyte macrophage colony-stimulating factor (GM-CSF) is a triggering molecule for this condition. Transcription factor Krüppel-like factor 6 (KLF6)-myeloid-specific conditional deficient mice exhibit this aortic phenotype when subjected to aortic inflammation. Mechanistically, KLF6 downregulates expression and secretion of GM-CSF. Administration of neutralizing antibody against GM-CSF prevents the condition in these mice. Conversely, administration of GM-CSF in combination with aortic inflammation to wild-type mice is sufficient to induce the phenotype, suggesting the general nature of effects. Moreover, patients with this condition show highly increased circulating levels of GM-CSF, which is also locally expressed in the dissected aorta. GM-CSF is therefore a key regulatory molecule causative of this aortopathy, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin

“…58 Clinically, a positive correlation between plasma concentrations of GM-CSF and intracranial aneurysms has been reported, 60 and circulating levels of GM-CSF are also elevated in patients with acute aortic dissection. 59 All of this evidence supports the concept that GM-CSF plays a major part in atherosclerosis and AAAs, in part by sustaining miR-181b levels. In future experiments beyond the present scope, it will be valuable to investigate these concepts further by manipulating the expression of GM-CSF.…”

“…57 Similarly, GM-CSF is abundant in human and mouse aortic aneurysms. 58 Furthermore, GM-CSF administration induced AAA development 57 and caused aortic dissection 59 in high-fat–fed Apoe −/− mice and CaCl 2 application/Ang II–infused C57Bl/6 mice, respectively. GM-CSF neutralization abrogated inflammatory aneurysm development and matrix-degrading activity in a Smad3 −/− mouse model.…”

Inhibition of KLF5–Myo9b–RhoA Pathway–Mediated Podosome Formation in Macrophages Ameliorates Abdominal Aortic Aneurysm

“…29 Moreover, myeloid-specific conditional KLF6-deficient mice reportedly exhibited aortic dissection and the presence of intramural macrophages because of the reduced expression and secretion of granulocyte-macrophage colony-stimulating factor. 30 Accordingly, myeloid-specific KLF5 knockout resulted in decreased aortic aneurysm formation and concomitantly reduced Myo9b expression in the present Ang II-or CaPO 4 -induced mouse AAA models. Taken together, our results indicate that KLF5 acts as an important regulator of aneurysm formation by promoting macrophage infiltration and migration.…”

Differential Regulation of Macrophage Glucose Metabolism by Macrophage Colony-stimulating Factor and Granulocyte-Macrophage Colony-stimulating Factor: Implications for 18F FDG PET Imaging of Vessel Wall Inflammation

“…Statistical analyses plaque macrophages susceptible to apoptosis and promotes the progression of advanced atherosclerotic plaques (22). GM-CSF also contributes to the development of aortic aneurysm (23), dissection, and intramural hematoma (24).…”