Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) by vascular smooth muscle cells. Deficiency in MMP3 reduces ECM damage and the susceptibility of mice to develop AAA. Here, we establish netrin-1 as a major signal that mediates the dynamic crosstalk between inflammation and chronic erosion of the ECM in AAA.
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We are thankful to Dr Adriana Heguy from the New York University Genome Technology Center for RNA sequencing (a resource partially supported by the Cancer Center Support Grant, P30CA016087, at the Laura and Isaac Perlmutter Cancer Center) and Zahid Dewan form the immunohistocore for sectioning assistance. This work was supported by the US National Institutes of Health (R00HL125667) to B.R. R01 DK097075, POI-HL114457, R01-HL109233, R01-DK109574, R01-HL119837 and R01-HL133900 to H.K.E.
The data and computer codes that support our findings are available from the corresponding author upon reasonable request. All RNA sequencing datasets are deposited in Gene Expression Omnibus (GEO)-accession number GSE118237 (GSM3323357 for the CLOUPE file used to generate Fig. 3a–d and f and the Supplementary Tables 1 and 2) and GSE118217 (GSM3321219 to GSM3321226 for each individual sample used to generate Fig. 4a and b, and Supplementary Figure 2a and b). A reporting summary for this Article is available as a Supplementary Information file.
Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-018-07495-1.
Hadi, Tarik; Boytard, Ludovic; Silvestro, Michele; Alebrahim, Dornazsadat; Jacob, Samson; Feinstein, Jordyn; Barone, Krista; Spiro, Wes; Hutchison, Susan; Simon, Russell; Rateri, Debra L.; Pinet, Florence; Fenyo, David; Adelman, Mark; Moore, Kathryn J.; Eltzschig, Holger K.; Daugherty, Alan; and Ramkhelawon, Bhama, "Macrophage-Derived Netrin-1 Promotes Abdominal Aortic Aneurysm Formation by Activating MMP3 in Vascular Smooth Muscle Cells" (2018). Physiology Faculty Publications. 132.