Aging impairs the neurovascular interface in the heart

Julian U.G. Wagner; Lukas S. Tombor; Pedro Felipe Malacarne; Lisa Maria Kettenhausen; Josefine Panthel; Haris Kujundzic; Nivethitha Manickam; Katja Schmitz; Maria Cipca; Kathrin A. Stilz; Ariane Fischer; Marion Muhly-Reinholz; Wesley T. Abplanalp; David John; Sarajo K. Mohanta; Christian Weber; Andreas J.R. Habenicht; Giulia K. Buchmann; Stephan Angendohr; Ehsan Amin; Katharina Scherschel; Nikolaj Klöcker; Malte Kelm; Dominik Schüttler; Sebastian Clauss; Stefan Günther; Thomas Boettger; Thomas Braun; Christian Bär; Minh Duc Pham; Jaya Krishnan; Susanne Hille; Oliver J. Müller; Tarik Bozoglu; Christian Kupatt; Eleonora Nardini; Selma Osmanagic-Myers; Christian Meyer; Andreas M. Zeiher; Ralf P. Brandes; Guillermo Luxán; Stefanie Dimmeler

doi:10.1126/science.ade4961

Aging impairs the neurovascular interface in the heart

Julian U.G. Wagner, Lukas S. Tombor, Pedro Felipe Malacarne, Lisa Maria Kettenhausen, Josefine Panthel, Haris Kujundzic, Nivethitha Manickam, Katja Schmitz, Maria Cipca, Kathrin A. Stilz, Ariane Fischer, Marion Muhly-Reinholz, Wesley T. Abplanalp, David John, Sarajo K. Mohanta, Christian Weber, Andreas J.R. Habenicht, Giulia K. Buchmann, Stephan Angendohr, Ehsan AminKatharina Scherschel, Nikolaj Klöcker, Malte Kelm, Dominik Schüttler, Sebastian Clauss, Stefan Günther, Thomas Boettger, Thomas Braun, Christian Bär, Minh Duc Pham, Jaya Krishnan, Susanne Hille, Oliver J. Müller, Tarik Bozoglu, Christian Kupatt, Eleonora Nardini, Selma Osmanagic-Myers, Christian Meyer, Andreas M. Zeiher, Ralf P. Brandes, Guillermo Luxán, Stefanie Dimmeler^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	897-906
Number of pages	10
Journal	Science
Volume	381
Issue number	6660
DOIs	https://doi.org/10.1126/science.ade4961
Publication status	Published - 25 Aug 2023

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Wagner, J. U. G., Tombor, L. S., Malacarne, P. F., Kettenhausen, L. M., Panthel, J., Kujundzic, H., Manickam, N., Schmitz, K., Cipca, M., Stilz, K. A., Fischer, A., Muhly-Reinholz, M., Abplanalp, W. T., John, D., Mohanta, S. K., Weber, C., Habenicht, A. J. R., Buchmann, G. K., Angendohr, S., ... Dimmeler, S. (2023). Aging impairs the neurovascular interface in the heart. Science, 381(6660), 897-906. https://doi.org/10.1126/science.ade4961

@article{62282cf6eed54cec85b2efc62e41dd31,

title = "Aging impairs the neurovascular interface in the heart",

abstract = "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.",

author = "Wagner, {Julian U.G.} and Tombor, {Lukas S.} and Malacarne, {Pedro Felipe} and Kettenhausen, {Lisa Maria} and Josefine Panthel and Haris Kujundzic and Nivethitha Manickam and Katja Schmitz and Maria Cipca and Stilz, {Kathrin A.} and Ariane Fischer and Marion Muhly-Reinholz and Abplanalp, {Wesley T.} and David John and Mohanta, {Sarajo K.} and Christian Weber and Habenicht, {Andreas J.R.} and Buchmann, {Giulia K.} and Stephan Angendohr and Ehsan Amin and Katharina Scherschel and Nikolaj Kl{\"o}cker and Malte Kelm and Dominik Sch{\"u}ttler and Sebastian Clauss and Stefan G{\"u}nther and Thomas Boettger and Thomas Braun and Christian B{\"a}r and Pham, {Minh Duc} and Jaya Krishnan and Susanne Hille and M{\"u}ller, {Oliver J.} and Tarik Bozoglu and Christian Kupatt and Eleonora Nardini and Selma Osmanagic-Myers and Christian Meyer and Zeiher, {Andreas M.} and Brandes, {Ralf P.} and Guillermo Lux{\'a}n and Stefanie Dimmeler",

year = "2023",

month = aug,

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doi = "10.1126/science.ade4961",

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journal = "Science",

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Wagner, JUG, Tombor, LS, Malacarne, PF, Kettenhausen, LM, Panthel, J, Kujundzic, H, Manickam, N, Schmitz, K, Cipca, M, Stilz, KA, Fischer, A, Muhly-Reinholz, M, Abplanalp, WT, John, D, Mohanta, SK, Weber, C, Habenicht, AJR, Buchmann, GK, Angendohr, S, Amin, E, Scherschel, K, Klöcker, N, Kelm, M, Schüttler, D, Clauss, S, Günther, S, Boettger, T, Braun, T, Bär, C, Pham, MD, Krishnan, J, Hille, S, Müller, OJ, Bozoglu, T, Kupatt, C, Nardini, E, Osmanagic-Myers, S, Meyer, C, Zeiher, AM, Brandes, RP, Luxán, G & Dimmeler, S 2023, 'Aging impairs the neurovascular interface in the heart', Science, vol. 381, no. 6660, pp. 897-906. https://doi.org/10.1126/science.ade4961

TY - JOUR

T1 - Aging impairs the neurovascular interface in the heart

AU - Wagner, Julian U.G.

AU - Tombor, Lukas S.

AU - Malacarne, Pedro Felipe

AU - Kettenhausen, Lisa Maria

AU - Panthel, Josefine

AU - Kujundzic, Haris

AU - Manickam, Nivethitha

AU - Schmitz, Katja

AU - Cipca, Maria

AU - Stilz, Kathrin A.

AU - Fischer, Ariane

AU - Muhly-Reinholz, Marion

AU - Abplanalp, Wesley T.

AU - John, David

AU - Mohanta, Sarajo K.

AU - Weber, Christian

AU - Habenicht, Andreas J.R.

AU - Buchmann, Giulia K.

AU - Angendohr, Stephan

AU - Amin, Ehsan

AU - Scherschel, Katharina

AU - Klöcker, Nikolaj

AU - Kelm, Malte

AU - Schüttler, Dominik

AU - Clauss, Sebastian

AU - Günther, Stefan

AU - Boettger, Thomas

AU - Braun, Thomas

AU - Bär, Christian

AU - Pham, Minh Duc

AU - Krishnan, Jaya

AU - Hille, Susanne

AU - Müller, Oliver J.

AU - Bozoglu, Tarik

AU - Kupatt, Christian

AU - Nardini, Eleonora

AU - Osmanagic-Myers, Selma

AU - Meyer, Christian

AU - Zeiher, Andreas M.

AU - Brandes, Ralf P.

AU - Luxán, Guillermo

AU - Dimmeler, Stefanie

PY - 2023/8/25

Y1 - 2023/8/25

N2 - 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.

AB - 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.

U2 - 10.1126/science.ade4961

DO - 10.1126/science.ade4961

M3 - Article

SN - 0036-8075

VL - 381

SP - 897

EP - 906

JO - Science

JF - Science

IS - 6660

ER -