PMID- 30479344 OWN - NLM STAT- MEDLINE DCOM- 20181231 LR - 20201218 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 9 IP - 1 DP - 2018 Nov 27 TI - Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. PG - 5022 LID - 10.1038/s41467-018-07495-1 [doi] LID - 5022 AB - 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. FAU - Hadi, Tarik AU - Hadi T AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. FAU - Boytard, Ludovic AU - Boytard L AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. FAU - Silvestro, Michele AU - Silvestro M AUID- ORCID: 0000-0003-1151-2215 AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. FAU - Alebrahim, Dornazsadat AU - Alebrahim D AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. FAU - Jacob, Samson AU - Jacob S AD - Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA. FAU - Feinstein, Jordyn AU - Feinstein J AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. FAU - Barone, Krista AU - Barone K AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. FAU - Spiro, Wes AU - Spiro W AD - Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA. FAU - Hutchison, Susan AU - Hutchison S AD - Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA. FAU - Simon, Russell AU - Simon R AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. FAU - Rateri, Debra AU - Rateri D AD - Department of Physiology and Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, 40506, USA. FAU - Pinet, Florence AU - Pinet F AUID- ORCID: 0000-0002-5471-1487 AD - University of Lille, Inserm U1167, Institut Pasteur de Lille, 59019, Lille, France. FAU - Fenyo, David AU - Fenyo D AD - Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA. FAU - Adelman, Mark AU - Adelman M AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. FAU - Moore, Kathryn J AU - Moore KJ AUID- ORCID: 0000-0003-2505-2547 AD - Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA. FAU - Eltzschig, Holger K AU - Eltzschig HK AD - Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. FAU - Daugherty, Alan AU - Daugherty A AD - Department of Physiology and Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, 40506, USA. FAU - Ramkhelawon, Bhama AU - Ramkhelawon B AD - Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA. bhama.ramkhelawon@nyumc.org. AD - Department of Cell Biology, New York University Medical Center, New York, NY, 10016, USA. bhama.ramkhelawon@nyumc.org. LA - eng GR - P30 CA016087/CA/NCI NIH HHS/United States GR - P01 HL131481/HL/NHLBI NIH HHS/United States GR - R01 HL133900/HL/NHLBI NIH HHS/United States GR - P01 HL114457/HL/NHLBI NIH HHS/United States GR - R01 HL109233/HL/NHLBI NIH HHS/United States GR - R00 HL125667/HL/NHLBI NIH HHS/United States GR - R01 DK097075/DK/NIDDK NIH HHS/United States GR - R01 HL146627/HL/NHLBI NIH HHS/United States GR - R01 DK111211/DK/NIDDK NIH HHS/United States GR - R01 DK109574/DK/NIDDK NIH HHS/United States GR - R01 HL119837/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20181127 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Membrane Proteins) RN - 0 (neogenin) RN - 158651-98-0 (Netrin-1) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Aortic Aneurysm, Abdominal/*metabolism MH - Calcium/metabolism MH - Gene Deletion MH - Hematopoiesis MH - Humans MH - Macrophages/*metabolism MH - Membrane Proteins MH - Mice, Inbred C57BL MH - Muscle, Smooth, Vascular/*pathology MH - Myocytes, Smooth Muscle/*enzymology MH - Netrin-1/deficiency/*metabolism PMC - PMC6258757 COIS- The authors declare no competing interests. EDAT- 2018/11/28 06:00 MHDA- 2019/01/01 06:00 PMCR- 2018/11/27 CRDT- 2018/11/28 06:00 PHST- 2018/02/14 00:00 [received] PHST- 2018/11/06 00:00 [accepted] PHST- 2018/11/28 06:00 [entrez] PHST- 2018/11/28 06:00 [pubmed] PHST- 2019/01/01 06:00 [medline] PHST- 2018/11/27 00:00 [pmc-release] AID - 10.1038/s41467-018-07495-1 [pii] AID - 7495 [pii] AID - 10.1038/s41467-018-07495-1 [doi] PST - epublish SO - Nat Commun. 2018 Nov 27;9(1):5022. doi: 10.1038/s41467-018-07495-1.