Periodic Reporting for period 1 - Neuroheart (The cardiac neurovascular interface in aging)
Période du rapport: 2022-10-01 au 2025-03-31
Aging is one of the key factors that negatively affects heart health. As people get older, the small blood vessels in the heart (the microcirculation) don’t function as well. Since nerves and blood vessels in the heart are closely connected, this study looked at how aging impacts this connection, known as the cardiac neurovascular interface.
We found that aging leads to fewer nerves in the heart and disrupts genes that are important for nerve control, especially those coming from blood vessels. Specifically, aging lowers the levels of a small molecule called microRNA 145 (miR-145), which normally helps keep certain proteins in check. One of these proteins is semaphorin-3A (Sema3a), a factor that pushes nerves away. When miR-145 levels drop, Sema3a levels increase, and this discourages nerve growth in the heart.
In experiments where we deleted miR-145 or artificially increased Sema3a levels, we saw fewer nerve fibers in the heart, which mirrored what we observe in older hearts. On the other hand, by removing old, non-functioning cells (called senescent cells) that build up with age, we were able to prevent this nerve loss. Removing these cells also lowered Sema3a levels, stabilized the heart’s rhythm, and reduced the chance of electrical problems in the heart.
In summary, our research suggests that the buildup of senescent cells as we age may play a key role in reducing nerve density in the heart, which in turn contributes to the decline in heart function often seen with aging.
We found that aging leads to fewer nerves in the heart and disrupts genes that are important for nerve control, especially those coming from blood vessels. Specifically, aging lowers the levels of a small molecule called microRNA 145 (miR-145), which normally helps keep certain proteins in check. One of these proteins is semaphorin-3A (Sema3a), a factor that pushes nerves away. When miR-145 levels drop, Sema3a levels increase, and this discourages nerve growth in the heart.
In experiments where we deleted miR-145 or artificially increased Sema3a levels, we saw fewer nerve fibers in the heart, which mirrored what we observe in older hearts. On the other hand, by removing old, non-functioning cells (called senescent cells) that build up with age, we were able to prevent this nerve loss. Removing these cells also lowered Sema3a levels, stabilized the heart’s rhythm, and reduced the chance of electrical problems in the heart.
In summary, our research suggests that the buildup of senescent cells as we age may play a key role in reducing nerve density in the heart, which in turn contributes to the decline in heart function often seen with aging.
We have completed the first part of the study (as published by Wagner et al in Science 2023). The publication investigates the relationship between aging and cardiovascular health, particularly focusing on the neurovascular interface in the heart. In particular, the research demonstrated the decline of nerve density in the heart and how this impacts overall cardiac health and includes work performed by all four work packages as follows.
Key findings
1. Dysregulation of innervation of the aging heart (WP 1): We observed significant alterations in the aging heart. We found that the density of sympathetic, parasympathetic and sensory nerves in the left ventricle of aging hearts significantly declines. Interestingly, there was no change in the right heart and even an augmented innervation in the atria, a finding which we are currently further exploring. Moreover, we have finalized histologic studies to elucidate the alignment of nerves with vessels, including lymphatics (unpublished).
2. Dysregulation of Neurovascular Genes (WP2): Aging was shown to dysregulate the expression of several genes involved in neuroregulation, particularly produced by the vasculature. We showed that the expression of the repulsive cue Semaphorin 3a (Sema3a) in endothelial cells can cause cardiac denervation showing that the disruption in endothelial gene regulation plays a critical role in the degradation of the neurovascular network, further contributing to cardiac dysfunction.
3. Role of MicroRNA 145 (miR-145) (WP2): The study identifies microRNA 145 (miR-145) as a crucial factor in maintaining nerve density within the heart. In aging hearts, miR-145 is downregulated, which leads to the derepression of semaphorin-3A (Sema3a), a neurorepulsive factor that inhibits nerve growth. Deletion of miR-145, which leads to increased Sema3a expression, or overexpression of Sema3a in endothelial cells, results in reduced axon density and altered heart rate variability in the heart. This reduction mirrors the nerve density loss and decreased heart rate variability seen in aged hearts, reinforcing the idea that miR-145 and Sema3a play a pivotal role in age-related neurovascular dysfunction.
4. Senescence and Cardiac Denervation (WP4): The study also identifies the accumulation of senescent cells as a key factor in age-related cardiac denervation. Senescent cells increase in number as the heart ages, coinciding with the reduction in nerve density. This accumulation appears to be a significant contributor to the overall decline in cardiac function with age.
5. Reversing Age-Related Effects (WP4): In a promising discovery, the removal of senescent cells in aged models rescues the heart from denervation. By eliminating these cells, we were able to reverse the increase in Sema3a expression, restore nerve density, and improve heart rate patterns. Additionally, the elimination of senescent cells reduced electrical instability in the heart, which is important for preventing arrhythmias and maintaining healthy cardiac rhythms.
Key findings
1. Dysregulation of innervation of the aging heart (WP 1): We observed significant alterations in the aging heart. We found that the density of sympathetic, parasympathetic and sensory nerves in the left ventricle of aging hearts significantly declines. Interestingly, there was no change in the right heart and even an augmented innervation in the atria, a finding which we are currently further exploring. Moreover, we have finalized histologic studies to elucidate the alignment of nerves with vessels, including lymphatics (unpublished).
2. Dysregulation of Neurovascular Genes (WP2): Aging was shown to dysregulate the expression of several genes involved in neuroregulation, particularly produced by the vasculature. We showed that the expression of the repulsive cue Semaphorin 3a (Sema3a) in endothelial cells can cause cardiac denervation showing that the disruption in endothelial gene regulation plays a critical role in the degradation of the neurovascular network, further contributing to cardiac dysfunction.
3. Role of MicroRNA 145 (miR-145) (WP2): The study identifies microRNA 145 (miR-145) as a crucial factor in maintaining nerve density within the heart. In aging hearts, miR-145 is downregulated, which leads to the derepression of semaphorin-3A (Sema3a), a neurorepulsive factor that inhibits nerve growth. Deletion of miR-145, which leads to increased Sema3a expression, or overexpression of Sema3a in endothelial cells, results in reduced axon density and altered heart rate variability in the heart. This reduction mirrors the nerve density loss and decreased heart rate variability seen in aged hearts, reinforcing the idea that miR-145 and Sema3a play a pivotal role in age-related neurovascular dysfunction.
4. Senescence and Cardiac Denervation (WP4): The study also identifies the accumulation of senescent cells as a key factor in age-related cardiac denervation. Senescent cells increase in number as the heart ages, coinciding with the reduction in nerve density. This accumulation appears to be a significant contributor to the overall decline in cardiac function with age.
5. Reversing Age-Related Effects (WP4): In a promising discovery, the removal of senescent cells in aged models rescues the heart from denervation. By eliminating these cells, we were able to reverse the increase in Sema3a expression, restore nerve density, and improve heart rate patterns. Additionally, the elimination of senescent cells reduced electrical instability in the heart, which is important for preventing arrhythmias and maintaining healthy cardiac rhythms.
Our research highlights the critical role of the neurovascular interface in maintaining cardiac health and demonstrates that aging-induced senescence plays a key role in disrupting nerve density in the heart. The findings suggest that senescence-driven denervation, mediated by dysregulation of miR-145 and Sema3a, contributes to the age-associated decline in cardiovascular function. Importantly, the study shows that removing senescent cells can restore nerve density and improve heart function, offering potential therapeutic strategies to counteract age-related cardiovascular diseases. This work did go beyond state of the art and sheds new light on the molecular mechanisms linking aging, the neurovascular system, and cardiovascular health, with potential implications for developing treatments that target cellular senescence to preserve heart health as people age.