Aging impairs the neurovascular interface in the heart

• 成果类型: Article
• 署名作者: Wagner, Julian U. G.; Tombor, Lukas S.; Malacarne, Pedro Felipe; Kettenhausen, Lisa-Maria; Panthel, Josefine; Kujundzic, Haris; Manickam, Nivethitha; Schmitz, Katja; Cipca, Maria; Stilz, Kathrin A.; Fischer, Ariane; Muhly-Reinholz, Marion; Abplanalp, Wesley T.; John, David; Mohanta, Sarajo K.; Weber, Christian; Habenicht, Andreas J. R.; Buchmann, Giulia K.; Angendohr, Stephan; Amin, Ehsan; Scherschel, Katharina; Kloecker, Nikolaj; Kelm, Malte; Schuettler, Dominik; Clauss, Sebastian; Guenther, Stefan; Boettger, Thomas; Braun, Thomas; Baer, Christian; Pham, Minh-Duc; Krishnan, Jaya; Hille, Susanne; Mueller, Oliver J.; Bozoglu, Tarik; Kupatt, Christian; Nardini, Eleonora; Osmanagic-Myers, Selma; Meyer, Christian; Zeiher, Andreas M.; Brandes, Ralf P.; Luxan, Guillermo; Dimmeler, Stefanie
• 署名单位: Goethe University Frankfurt; German Centre for Cardiovascular Research; Goethe University Frankfurt; University of Munich; University of Munich; German Centre for Cardiovascular Research; Maastricht University; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf Hospital; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf; Heinrich Heine University Dusseldorf Hospital; University of Munich; University of Munich; University of Munich; Max Planck Society; Hannover Medical School; Hannover Medical School; Goethe University Frankfurt; Goethe University Frankfurt Hospital; University of Kiel; Schleswig Holstein University Hospital; German Centre for Cardiovascular Research; Technical University of Munich; Medical University of Vienna
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10832
• DOI: 10.1126/science.ade4961
• 发表日期: 2023-08-25
• 页码: 897-905
• 关键词: sympathetic innervation; nervous-system; cells

摘要

Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align with vessels, we assessed the impact of aging on the cardiac neurovascular interface. We report that aging reduces nerve density in the ventricle and dysregulates vascular-derived neuroregulatory genes. Aging down-regulates microRNA 145 (miR-145) and derepresses the neurorepulsive factor semaphorin-3A. miR-145 deletion, which increased Sema3a expression or endothelial Sema3a overexpression, reduced axon density, mimicking the aged-heart phenotype. Removal of senescent cells, which accumulated with chronological age in parallel to the decline in nerve density, rescued age-induced denervation, reversed Sema3a expression, preserved heart rate patterns, and reduced electrical instability. These data suggest that senescence-mediated regulation of nerve density contributes to age-associated cardiac dysfunction.