Abstract 12226: Aging Impairs the Neuro-Vascular Interface in the Heart

Medientyp: E-Artikel

Titel: Abstract 12226: Aging Impairs the Neuro-Vascular Interface in the Heart

Beteiligte: Wagner, Julian U; Tombor, Lukas; Malacarne, Pedro F; Manickam, Nivethitha; Abplanalp, Wesley T; John, David; Buchmann, Giulia Karolin K; Angendohr, Stephan; Amin, Ehsan; Scherschel, Katharina; Nikolaj, Klöcker; Kelm, Malte; Schüttler, Dominik; Clauss, Sebastian; Guenther, Stefan; Braun, Thomas; Boettger, Thomas; Baer, Christian; Pham, Minh-Duc; Krishnan, Jaya; Hille, Susanne S; Mueller, Oliver; Bozoglu, Tarik; Kupatt, Christian; [...]

Erschienen: Ovid Technologies (Wolters Kluwer Health), 2023

Sprache: Englisch

DOI: 10.1161/circ.148.suppl_1.12226

ISSN: 1524-4539; 0009-7322

Schlagwörter: Physiology (medical) ; Cardiology and Cardiovascular Medicine

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Beschreibung: Aging is a major risk factor for impaired cardiovascular function. The aging heart is characterized by vascular dysfunction, increased hypertrophy, fibrosis and electrophysiological alterations. However, the interaction between the different age-associated changes in cardiac remodelling is poorly define. Since vessels are aligned with nerves, and this interplay is critical for tissue homeostasis, we investigated whether an impairment of the neuro-vascular interface may contribute to age-associated pathologies in the heart. We show that aging reduces sympathetic and sensory nerve fibers, which both align to arteries and arterioles. Aging induced a dysregulation of vascular-derived neuro-regulatory genes, especially the axon repellent factor Sema3A, which was augmented by 2.4±0.1-fold in old heart endothelial cells. Consistently, endothelial Sema3a overexpression reduced axon density in vivo, thus mimicking the observed aged heart phenotype. Since cellular senescence was induced at the same time point when nerve density declined (16 months of age) and senescence endothelial cells showed a higher expression of Sema3a, we hypothesized that endothelial senescence may contribute to cardiac denervation. Indeed, supernatants of senescent endothelial cells reduced neurite outgrowth in vitro in a Sema3A-dependent manner. In vivo studies further confirmed that endothelial-specific induction of senescence by overexpression of Progerin induced left ventricular denervation and induced Sema3a expression. By contrast, the pharmacological removal of senescent cells by the senolytic drugs dasatinib and quercetin rescued age-induced denervation and prevented the age-induced induction of endothelial Sema3a expression. Functional studies additionally demonstrated that endothelial senescence reduced heart rate variability, while senolytics preserved heart rate variability, restored age-associated declines in sympathetic and parasympathetic activity and reduced age-associated increase in arrhythmias. These data suggest that senescence-associated regulation of neuro-regulatory genes in endothelial cells is associated with reduced nerve density and, thereby, contributes to age-associated cardiac dysfunction.

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