Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins

Alba de Juan, Louise Madeleine Ince, Robert Pick, Chien Sin Chen, Filippo Molica, Gabriele Zuchtriegel, Chen Wang, Dachuan Zhang, David Druzd, Maximilian E.T. Hessenauer, Graziano Pelli, Isa Kolbe, Henrik Oster, Colette Prophete, Sophia Martina Hergenhan, Urs Albrecht, Jürgen Ripperger, Eloi Montanez, Christoph A. Reichel, Oliver SoehnleinBrenda R. Kwak, Paul S. Frenette, Christoph Scheiermann

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

BACKGROUND: The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied. METHODS: We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α-induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene Bmal1 (also known as Arntl) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process. RESULTS: In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type-specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of β2-adrenergic receptor signaling. Loss of the core clock gene Bmal1 in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type-specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence. CONCLUSIONS: Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day-dependent vessel type-specific thrombotic events.

Original languageEnglish (US)
Pages (from-to)1100-1114
Number of pages15
JournalCirculation
Volume140
Issue number13
DOIs
StatePublished - Sep 24 2019

Fingerprint

Blood Vessels
Veins
Leukocytes
Arteries
Inflammation
Periodicity
Microvessels
Adrenergic Receptors
Circadian Clocks
Cell Adhesion Molecules
Leukocyte Count
Fluorescence Microscopy
Genes
Thrombosis
Blood Platelets
Endothelial Cells
Tumor Necrosis Factor-alpha
Pharmacology
Incidence

Keywords

  • cell adhesion molecules
  • circadian rhythm
  • sympathetic nervous system
  • thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

de Juan, A., Ince, L. M., Pick, R., Chen, C. S., Molica, F., Zuchtriegel, G., ... Scheiermann, C. (2019). Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins. Circulation, 140(13), 1100-1114. https://doi.org/10.1161/CIRCULATIONAHA.119.040232

Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins. / de Juan, Alba; Ince, Louise Madeleine; Pick, Robert; Chen, Chien Sin; Molica, Filippo; Zuchtriegel, Gabriele; Wang, Chen; Zhang, Dachuan; Druzd, David; Hessenauer, Maximilian E.T.; Pelli, Graziano; Kolbe, Isa; Oster, Henrik; Prophete, Colette; Hergenhan, Sophia Martina; Albrecht, Urs; Ripperger, Jürgen; Montanez, Eloi; Reichel, Christoph A.; Soehnlein, Oliver; Kwak, Brenda R.; Frenette, Paul S.; Scheiermann, Christoph.

In: Circulation, Vol. 140, No. 13, 24.09.2019, p. 1100-1114.

Research output: Contribution to journalArticle

de Juan, A, Ince, LM, Pick, R, Chen, CS, Molica, F, Zuchtriegel, G, Wang, C, Zhang, D, Druzd, D, Hessenauer, MET, Pelli, G, Kolbe, I, Oster, H, Prophete, C, Hergenhan, SM, Albrecht, U, Ripperger, J, Montanez, E, Reichel, CA, Soehnlein, O, Kwak, BR, Frenette, PS & Scheiermann, C 2019, 'Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins', Circulation, vol. 140, no. 13, pp. 1100-1114. https://doi.org/10.1161/CIRCULATIONAHA.119.040232
de Juan, Alba ; Ince, Louise Madeleine ; Pick, Robert ; Chen, Chien Sin ; Molica, Filippo ; Zuchtriegel, Gabriele ; Wang, Chen ; Zhang, Dachuan ; Druzd, David ; Hessenauer, Maximilian E.T. ; Pelli, Graziano ; Kolbe, Isa ; Oster, Henrik ; Prophete, Colette ; Hergenhan, Sophia Martina ; Albrecht, Urs ; Ripperger, Jürgen ; Montanez, Eloi ; Reichel, Christoph A. ; Soehnlein, Oliver ; Kwak, Brenda R. ; Frenette, Paul S. ; Scheiermann, Christoph. / Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins. In: Circulation. 2019 ; Vol. 140, No. 13. pp. 1100-1114.
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T1 - Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins

AU - de Juan, Alba

AU - Ince, Louise Madeleine

AU - Pick, Robert

AU - Chen, Chien Sin

AU - Molica, Filippo

AU - Zuchtriegel, Gabriele

AU - Wang, Chen

AU - Zhang, Dachuan

AU - Druzd, David

AU - Hessenauer, Maximilian E.T.

AU - Pelli, Graziano

AU - Kolbe, Isa

AU - Oster, Henrik

AU - Prophete, Colette

AU - Hergenhan, Sophia Martina

AU - Albrecht, Urs

AU - Ripperger, Jürgen

AU - Montanez, Eloi

AU - Reichel, Christoph A.

AU - Soehnlein, Oliver

AU - Kwak, Brenda R.

AU - Frenette, Paul S.

AU - Scheiermann, Christoph

PY - 2019/9/24

Y1 - 2019/9/24

N2 - BACKGROUND: The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied. METHODS: We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α-induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene Bmal1 (also known as Arntl) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process. RESULTS: In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type-specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of β2-adrenergic receptor signaling. Loss of the core clock gene Bmal1 in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type-specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence. CONCLUSIONS: Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day-dependent vessel type-specific thrombotic events.

AB - BACKGROUND: The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied. METHODS: We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α-induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene Bmal1 (also known as Arntl) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process. RESULTS: In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type-specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of β2-adrenergic receptor signaling. Loss of the core clock gene Bmal1 in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type-specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence. CONCLUSIONS: Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day-dependent vessel type-specific thrombotic events.

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KW - circadian rhythm

KW - sympathetic nervous system

KW - thrombosis

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