Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Aortic wall inflammation and subsequent degradation of extracellular matrix (ECM) proteins, especially the elastin breakage, are the determining factors for the development of AAA. Vascular inflammation, particularly macrophage infiltration and inflammatory SMC phenotype, causes the production of proteolytic enzymes that disrupt ECM homeostasis leading to a weakened vessel wall and consequently AAA formation. However, there is a critical knowledge gap concerning the mechanism(s) or key factor(s) controlling both the vascular inflammation and the ECM dysregulation. Our exciting preliminary data indicate that dedicator of cytokinesis 2 (DOCK2) plays a central role in the induction of inflammatory SMC phenotype and AAA formation. DOCK2 deficiency (DOCK2-/-) in mice significantly attenuates AAA formation (with decreased elastin breakage and improved artery wall integrity) and diminishes the induction of inflammatory SMC phenotype. Consequently, DOCK2-/- inhibits the expression of monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-2 (MMP2) in SMCs while restoring contractile SMC markers. Consistently, the macrophage infiltration in aneurysm arterial media is blocked in DOCK2-/- mice. Moreover, DOCK2 expression is associated with aneurysm formation in human patients. These data strongly support a novel hypothesis that DOCK2 induces inflammatory SMC phenotype leading to vascular inflammation, elastin breakage, and consequently AAA formation. Using primary mouse and human SMCs, in vivo DOCK2 SMC-, macrophage-, and T cell- specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) determine the mechanisms by which DOCK2 regulates inflammatory SMC phenotype; and 2) test the hypothesis that DOCK2 promotes AAA formation by stimulating inflammatory SMC phenotype in vivo. Successful completion of the proposed studies will establish novel mechanisms regulating SMC inflammatory phenotype and vascular inflammation, which are likely to advance our understanding of the AAA formation and ultimately lead to novel strategies for developing effective therapeutics to treat AAA.
Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Aortic wall inflammation and subsequent degradation of extracellular matrix proteins, especially the elastic lamellae of the media, are the determining factors for the development of AAA. In this application, a combination of molecular, cellular, and genetic approaches with gain-of- and loss-of-function studies will be used to establish novel mechanisms by which dedicator of cytokinesis 2 promotes AAA formation by inducing inflammatory vascular smooth muscle phenotype. The outcome of the project may lead to the development of new strategies for the prevention and therapy of AAA.
