| Autor: |
Arévalo Martínez M; Vascular Physiology Environment, Department of Experimental Medical Science, Lund University, Lund, Sweden., Ritsvall O; Vascular Physiology Environment, Department of Experimental Medical Science, Lund University, Lund, Sweden., Bastrup JA; Vascular Biology Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Celik S; Molecular Cardiology, Department of Clinical Sciences, Lund University, Lund, Sweden., Jakobsson G; Department of Translational Medicine, Lund University, Malmö, Sweden., Daoud F; Vascular Physiology Environment, Department of Experimental Medical Science, Lund University, Lund, Sweden., Winqvist C; Vascular Physiology Environment, Department of Experimental Medical Science, Lund University, Lund, Sweden., Aspberg A; Rheumatology and Molecular Skeletal Biology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Rippe C; Vascular Physiology Environment, Department of Experimental Medical Science, Lund University, Lund, Sweden., Maegdefessel L; Department of Medicine, Karolinska Institute, Stockholm, Sweden, and.; Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar - Technical University Munich (TUM), Munich, Germany., Schiopu A; Department of Translational Medicine, Lund University, Malmö, Sweden.; Department of Internal Medicine, Skåne University Hospital Lund, Lund, Sweden, and.; Nicolae Simionescu Institute of Cellular Biology and Pathology, Bucharest, Romania., Jepps TA; Vascular Biology Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Holmberg J; Vascular Physiology Environment, Department of Experimental Medical Science, Lund University, Lund, Sweden., Swärd K; Vascular Physiology Environment, Department of Experimental Medical Science, Lund University, Lund, Sweden., Albinsson S; Vascular Physiology Environment, Department of Experimental Medical Science, Lund University, Lund, Sweden. |
| Abstrakt: |
Inadequate adaption to mechanical forces, including blood pressure, contributes to development of arterial aneurysms. Recent studies have pointed to a mechanoprotective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we identified reduced expression of YAP1 in human aortic aneurysms. Vascular SMC-specific knockouts (KOs) of YAP/TAZ were thus generated using the integrin α8-Cre (Itga8-Cre) mouse model (i8-YT-KO). i8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within 2 weeks of KO induction and in smaller arteries at later times. The vascular specificity of Itga8-Cre circumvented gastrointestinal effects. Aortic aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of proteoglycans and immune cell populations. RNA sequencing, proteomics, and myography demonstrated decreased contractile differentiation of SMCs and impaired vascular contractility. This associated with partial loss of myocardin expression, reduced blood pressure, and edema. Mediators in the inflammatory cGAS/STING pathway were increased. A sizeable increase in SOX9, along with several direct target genes, including aggrecan (Acan), contributed to proteoglycan accumulation. This was the earliest detectable change, occurring 3 days after KO induction and before the proinflammatory transition. In conclusion, Itga8-Cre deletion of YAP and TAZ represents a rapid and spontaneous aneurysm model that recapitulates features of human abdominal aortic aneurysms. |
