Involvement of FAK in aortic dissection: potential role in aortic interstitial cells

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Abstract Background Aortic dissection (AD) is a fatal disease where the intimomedial layer of the aorta suddenly fail. Although it is widely accepted that hemodynamic stress on the aortic wall triggers its destruction that is further promoted by inflammatory response as exemplified by the infiltration of neutrophils and macrophages, molecular mechanism is unknown for the link of aortic wall stress, inflammation and tissue destruction. In general, mechanical stress to the tissue is converted to the cellular response through the cell adhesion molecules and the activation of focal adhesion kinase (Fak). Although it has been reported that Fak is involved in pathogenesis of aortic aneurysm by promoting migration and activation of macrophages, its role in AD is unknown. We hypothesized that Fak may be involved in AD pathogenesis. Purpose We investigated the involvement of Fak in AD pathogenesis, focusing on its role in inflammatory cells. Methods and results We created a mouse model of AD by continuous infusion of beta-aminopropionitrile, a collagen crosslink inhibitor, and angiotensin II (BAPN + Ang II). Immunostaining for activated Fak revealed that Fak was not activated in normal aorta, but was activated in the infiltrating inflammatory cells and in interstitial cells of the aortic wall after AD development. We examined the role of Fak by oral administration of PND-1186, a specific Fak inhibitor, in mouse AD model. Vehicle-treated group showed 63.6% mortality, whereas PND-1186-treated group showed 20% mortality (P<0.01, n=20 for each group) in 14 days of the observational period. The aortic arch lesion, the most critical part in AD, was improved from 1.96±0.41 mm in vehicle group to 0.66±0.29 mm in PND group (P<0.05). We next examined the cell type-specific role of Fak in AD by creating macrophage and granulocyte-specific deletion of Fak driven by LysM-Cre and floxed Fak system. Unexpectedly, the genetic deletion of Fak in macrophages and granulocytes had no impact on the mortality nor the severity of AD. Conclusions These findings proved that Fak plays a critical role in AD progression and death. Because Fak is dispensable for macrophages and granulocytes, other cell types, possibly aortic wall interstitial cells, may be regulated by Fak in AD pathogenesis. Deciphering the role of Fak would provide the fundamental understanding of AD pathogenesis. Funding Acknowledgement Type of funding sources: None.