Interactions Between Innervation, Vascular Aging, and Loss of Capillary Density in the Heart – Fight Aging!

One noted aspect of vascular aging is that the processes of angiogenesis become less effective with age, and as a consequence aged tissues lose capillary density. This harms function by reducing the supply of nutrients and oxygen to energy-hungry tissues such as muscles and brain, as well as putting stress on the remaining vasculature due to changes in the dynamics of blood flow. Accompanying this form of vascular aging is a progressive innervation, a loss of peripheral nervous system connections. These two complex processes interact strongly with one another, given the proximity of blood vessels and nerves, and signaling that passes back and forth between the cell types involved.

In today’s open access commentary, researchers discuss recent findings regarding the interaction of blood vessel aging and peripheral nervous system aging, with a focus on the heart, where the consequences of these processes include various forms of arrhythmia. Interestingly, innervation precedes loss of capillary density, something that might form the basis for further investigation in and of itself, given the importance of this loss to tissue function. The primary result, however, is that researchers found one specific signal that appears to be released by endothelial cells in aged tissues, and which is disruptive to peripheral nerve formation and maintenance. This gives a target for drug development and further research into this form of degenerative aging.

Endothelial cell dysfunction: the culprit for cardiac denervation in aging?

During cardiac development, nerves grow in close anatomic proximity to blood vessels due to their need for oxygen and nutrients. Vice versa, blood vessels require closeness to nerves for tight control of vasodilation and vasoconstriction. However, their interdependence also means that malfunction of one cell type may result in dysregulation of the other. Two important sources of cardiac innervation are the parasympathetic and sympathetic nervous systems, and under- or hyper-activity of either system can lead to heart failure or arrhythmias. One common condition associated with autonomic nervous system deterioration and a predilection for cardiac arrhythmias is aging. Researchers recently demonstrated that aging-dependent vascular endothelial cell dysfunction reduces the density of neuronal axons in the heart, which in turn increases the risk of arrhythmias.

For these groundbreaking studies, researchers utilized 18-20-month-old male and female wild-type (WT) mice as the primary model of aging. Compared to young (3-month-old) mice, old mice exhibited ventricular diastolic dysfunction. Immunohistochemical staining of heart cross-sections revealed that all three major types of nerve fibers – parasympathetic, sympathetic, and sensory – were decreased in old vs. young mice. In conjunction, there was a higher incidence of inducible ventricular tachycardia in hearts isolated from old vs. young mice.

A time-course experiment revealed that nerve degeneration presented at 16 months prior to the onset of capillary rarefaction at 20 months – suggesting that nerve degeneration is not caused by loss of capillaries but rather may be due to alterations in vascular-derived neuroguidance cues. RNA sequencing (RNA-seq) of cardiac endothelial cells (ECs) isolated from old mice revealed upregulation of genes encoding pathways involved in neuronal death and axon injury, in particular semaphorin 3A (Sema3a). Interestingly, prior work had revealed that both deletion and overexpression of Sema3a can cause ventricular arrhythmias and sudden death in mutant mice. The researchers uncovered a new mechanism that involves aging ECs releasing more Sema3a, which reduces neuronal axon density in the heart, thereby promoting ventricular arrhythmias.