Ageing impairs the neuro-vascular interface in the heart

Abstract

Aging is a major risk factor for impaired cardiovascular health. The aging myocardium is characterized by electrophysiological dysfunctions such as a reduced heart rate variability. These alterations can be intrinsic within cardiomyocytes, but might be modulated by the cardiac autonomic nervous system, as well1. It is known that nerves align with vessels during development2, but the impact of aging on the cardiac neuro-vascular interface is unknown. Here, we report that aging reduces nerve density specifically in the left ventricle and dysregulates vascular-derived neuro-regulatory genes. Aging leads further to a down-regulation of miR-145 and de-repression of the neuro-repulsive factor Semaphorin-3A. miR-145 deletion increased Sema3a expression and reduced axon density, thus mimicking the observed aged heart phenotype. Removal of senescent cells, which accumulated with chronological age while nerve density declined, rescued from age-induced dennervation, reduced Sema3a expression and preserved heart rate variability. These data suggest that senescence-associated regulation of neuro-regulatory genes contributes to a declined nerve density of the aging heart and thereby to a reduced heart rate variability.

The aging-induced long non-coding RNAMIRIALcontrols endothelial cell and mitochondrial function

“…The related data are available on Gene Expression Omnibus (accession number GSE237230). RNA-sequencing data of cardiac endothelial cells derived from young and aged mice was published previously and is available online 44 .…”

Advances in cardiac tissue engineering and heart‐on‐a‐chip

“…Recent imaging studies, reveal their elaborate positioning intertwined with cardiomyocytes within the myocardium 18 . Disregulation of intrinsic cardiac neuron activity can lead to diseases such as arrhythmia and may be one of the causes of loss of cardiac function during ageing 19 . The contraction of the heart is defined by cardiomyocyte orientation and a complex built‐in electrophysiological system that translates the microscopic movement of individual cardiomyocytes into macroscopic organ contraction.…”

“…18 Disregulation of intrinsic cardiac neuron activity can lead to diseases such as arrhythmia and may be one of the causes of loss of cardiac function during ageing. 19 The contraction of the heart is defined by cardiomyocyte orientation and a complex built-in electrophysiological system that translates the microscopic movement of individual cardiomyocytes into macroscopic organ contraction. In addition, mechanical signals, such as changes in preload, afterload 20 or extracellular matrix (ECM) stiffness, 21,22 can alter cardiomyocyte contractile behavior, based on the Frank-Starling Law of the heart and mechanosensing mechanisms.…”

“…156 Yet, later studies identified the crucial role of FBs in creating functional cardiac patches, 157 which subsequently led to their widespread integration into cardiac tissue engineering protocols, both in vitro and in vivo. 19,[158][159][160][161][162][163][164] We had previously shown that cardiac tissues derived from iPSC-CMs containing 75% iPSC-CMs and CD90+ FB-like cells 164 exhibited improved matrix remodeling and functional characteristics compared to CM mono-cultures. Moreover, we observed that iPSC-CMs could not generate contractile forces within tissues without cardiac fibroblasts.…”

“…In the early stages of cardiac tissue engineering research, they were often viewed as undesirable and were systematically eliminated through a series of pre‐plating procedures 156 . Yet, later studies identified the crucial role of FBs in creating functional cardiac patches, 157 which subsequently led to their widespread integration into cardiac tissue engineering protocols, both in vitro and in vivo 19,158‐164 . We had previously shown that cardiac tissues derived from iPSC‐CMs containing 75% iPSC‐CMs and CD90+ FB‐like cells 164 exhibited improved matrix remodeling and functional characteristics compared to CM mono‐cultures.…”