Abdominal aortic aneurysm (AAA) is a common vascular disorder associated with inflammation and upregulation of matrix-metalloproteinases (MMP), which cause the local degradation of the extracellular matrix (ECM) culminating in life-threatening rupture of the excessively damaged aortic wall. The incidence of AAA is unacceptably high. Despite progress in primary preventive measures, AAA still accounts for > 13000 deaths annually due to ruptured AAA in the United States. Because major knowledge gaps in the mechanisms that contribute to sustained ECM degradation persist, there is currently no drug-based therapy to circumvent AAA, surgery is the only alternative to overcome or delay the burden of patients. Previous work from our group has identified an instrumental role for the neuronal guidance cue, netrin-1 in fostering vascular inflammation. Transmural macrophage infiltration in the damaged vascular wall is a key hallmark of AAA. Their role in sustaining ECM degradation in AAA remains poorly understood. The objective of this proposal is to characterize the role of netrin-1 in sustaining ECM destruction in AAA. The central hypothesis is that macrophage-derived netrin-1 is a pathological signal capable of fueling MMP activation in vascular smooth muscle cells (VSMC) and the disruption of this cross-talk mechanism protects against pathological vascular remodeling in AAA. Our rationale is based on important observations made during K99/R00 award that the absence of netrin-1 in hematopoietic cells (Ntn1-/-) protects against AAA development and elastin fragmentation. Single cell RNA sequencing revealed that netrin-1 was harbored in transmural macrophages. Importantly, RNA sequencing of WT and Ntn1-/- aortas identified that MMP3 was downregulated in the VSMC in netrin-1-deficient mice. In our specific aims, will use novel mouse models of tissue-specific or conditional deletion of netrin-1 in macrophages, deletion of MMP3 and neogenin (the receptor of netrin-1) in VSMC to determine how this guidance cue orchestrates a series of events that lead to sustained ECM degradation by fueling the supply of catalytic enzymes to the abdominal tissue. The proposed research is innovative because we investigate the role netrin-1 in mediating cross-talk startegies and deleterious vascular remodeling, a heretofore-unexamined mechanism in AAA. Upon conclusion, we will understand the role of netrin-1 in synchronizing ECM damage via complex mechanisms in AAA. This contribution is significant since we will test whether targeting netrin-1 after AAA is established (inducible deletion murine models) can reverse the degradation of the ECM and prevent rupture. In this translational approach, our data will pave the way for the development of promising preventive therapeutic strategies aimed at targeting netrin-1 or antagonizing its signaling events to prevent AAA.
Abdominal aortic aneurysm (AAA) enriched with transmural macrophages (M) prone to high risk of rupture. There is a need to clarify the role of these cells in the pathogenesis of AAA. Our strong preliminary data indicates that M can coordinate with vascular smooth muscle cells to sustain the degradation of the aorta. We propose to use powerful mouse coupled with state-of-the-art approaches to delve into the mechanisms of how M can impact AAA thereby proposing novel promising strategies for treating this complex deadly disease.
