Summary Abdominal Aortic Aneurysm (AAA) is an aggressive vascular disease that carries a significant human death toll. The inflammatory AAA microenvironment mainly driven by aortic macrophages (MØ) enables AAA progression by promoting extracellular matrix (ECM) degradation leading to a progressive dilatation of the aortic wall which will eventually rupture and cause death. While our findings in the previous funding cycle have elaborated on the effector roles of MØ within the AAA mayhem, the upstream mechanisms derived from the expanding AAA that subsequently induce MØ reprograming remain poorly defined. Our rationale is based on compelling new preliminary results using single-cell RNA sequencing and functional studies of human and mice AAA that demonstrate that the homo-dimeric activation of cadherin11 (Cdh11) with itself amplifies aortic MØ inflammatory functions by promoting the discharge of proteolytic factors in the AAA sac. The activation of Cdh11 expressed by fibroblasts triggers the expression of Csf1 via YapTaz/Tead1 that acts on MØ via its receptor Csf1r. We show that inhibition of Cdh11 with a novel small molecule inhibitor prevents mice from developing AAA by tempering the MØ inflammatory and proteolytic responses ensuing the inhibition of ECM degradation. We observed that Cdh11 controls the level of membrane-bound and secreted variants of Csf1 (mCsf1, sCsf1) which could supervise the intensity of MØ inflammatory responses at distinct sites within the AAA sac. We postulate that within the expanding AAA sac, local endotensions activate fibroblast-Cdh11 thereon fostering the local secretion of Csf1 and its variants through YapTaz/Tead1 dependent pathways. This fuels the amplification of deleterious MØ responsescreatingacontinuumthatsustainsECMdegradationandpromoteAAAdevelopmentandrupture. We will concert with experts in the fields of Cdh11 and Csf1 to address our hypothesis in 3 specific aims. In aim 1, we will delineate the impact of conditionally deleting Csf1 in Cdh11 fibroblasts in AAA and study the effects on MØ phenotype and activation. Transcriptome and epitope mapping will provide new mechanistic insights imposed by Cdh11 in AAA. In aim 2, we will define whether Cdh11 inhibition can regulate MØ proliferation, clonality and plasticity in AAA by using sophisticated MØ conditional mice (Confetti, Fucci). In aim 3, we will interrogate the mechanisms underlying the mechanical activation of Cdh11 and test the role of YapTaz/Tead1 in regulating Csf1 and its variants in in vitro approaches. The distinct role of mCsf1 and sCsf1 and their impact on MØ activation will be directly tested in AAA using transgenic mice overexpressing these isoforms. Spatial transcriptomic analysis of human AAA will elucidate the cartography of Cdh11/MØ interactions and their impact on neighboring cell clusters in AAA. This proposed research is provocative and innovative as the role of Cdh11 in AAA is undefined. The use of clinical samples will provide solid pat...