{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:58:43Z","timestamp":1790017123036,"version":"4.0.1"},"reference-count":76,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T00:00:00Z","timestamp":1750377600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,6,20]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Aortic dissection (AD) is the separation of medial layers of the aorta and is a major cause of death in patients with connective tissue disorders such as Marfan syndrome. However, molecular triggers instigating AD, its temporospatial progression, and how vascular cells in each vessel layer interact and participate in the pathological process remain incompletely understood. To unravel the underlying molecular mechanisms of AD, we generated a spontaneous AD mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We incorporated a novel missense variant (p.G234D) in\n                      <jats:italic toggle=\"yes\">FBN1<\/jats:italic>\n                      , the gene for fibrillin-1, identified in a patient with nonsyndromic familial AD into mice using the CRISPR\/Cas9 (clustered regularly interspaced short palindromic repeats\/CRISPR-associated protein 9) system. We performed molecular pathological analyses of the aortic lesions by histology, immunofluorescence staining, electron microscopy, synchrotron-based imaging, and single-cell RNA sequencing. Biochemical analysis was performed to examine the binding capacity of mutant human FBN1\n                      <jats:sup>G234D<\/jats:sup>\n                      (fibrillin 1 Gly234Asp) protein to LTBPs (latent TGF\u03b2 [transforming growth factor-beta] binding proteins), and signaling pathways in the mutant aortic wall were examined by the Western blot analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Fifty percent of the\n                      <jats:italic toggle=\"yes\">Fbn1<\/jats:italic>\n                      <jats:sup>G234D\/G234D<\/jats:sup>\n                      mutant mice died within 5 weeks of age from multiple intimomedial tears that expanded longitudinally and progressed to aortic rupture accompanied by massive immune cell infiltration.\n                      <jats:italic toggle=\"yes\">Fbn1<\/jats:italic>\n                      <jats:sup>G234D\/G234D<\/jats:sup>\n                      endothelial cells exhibited altered mechanosensing with loss of parallel alignment to blood flow and upregulation of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) as early as 1 week of age. Single-cell RNA sequencing, validated by immunostaining, revealed a cluster of monocyte\/macrophage predominantly in the intima at 3 weeks of age before the dissection, and the second cluster of macrophages increased during the progression of intimomedial tears, exhibiting strong CCR2+ (C-C motif chemokine receptor 2 positive) and both M1- and M2-like features. Consistently, upregulation of MMP2\/9 (matrix metalloproteinase 2 and 9) was observed. Biochemically, FBN1\n                      <jats:sup>G234D<\/jats:sup>\n                      lost the ability to bind to LTBP-1, -2, and -4, resulting in the downregulation of TGF\u03b2 signaling in the aortic wall.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>We show that interactions involving endothelial cells and macrophages\/monocytes in the intima, where the extracellular matrix (ECM) microenvironment contains reduced TGF\u03b2 signaling, contribute to the initiation of AD. Our novel AD mouse model provides a unique opportunity to identify target molecules involved in the intimomedial tears that can be utilized for the development of therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.326230","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T05:00:34Z","timestamp":1747198834000},"page":"26-42","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"title":["Novel Aortic Dissection Model Links Endothelial Dysfunction and Immune Infiltration"],"prefix":"10.1161","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0363-8865","authenticated-orcid":true,"given":"Kenichi","family":"Kimura","sequence":"first","affiliation":[{"name":"Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (K.K., E.M., K.A., M.A.A.S., M.T.R.D.C.C., E.R., R.I., H.Y.), University of Tsukuba, 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