Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis

Annas Al-Sharea, Man K.S. Lee, Alexandra Whillas, Danielle L. Michell, Waled A. Shihata, Alyce J. Nicholls, Olivia D. Cooney, Michael J. Kraakman, Camilla Bertuzzo Veiga, Ann Maree Jefferis, Kristy Jackson, Prabhakara R. Nagareddy, Gavin Lambert, Connie H.Y. Wong, Karen L. Andrews, Geoff A. Head, Jaye Chin-Dusting, Andrew J. Murphy

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the b-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.

Original languageEnglish
Pages (from-to)456-467
Number of pages12
JournalHaematologica: the hematology journal
Volume104
Issue number3
DOIs
Publication statusPublished - 28 Feb 2019

Cite this

Al-Sharea, Annas ; Lee, Man K.S. ; Whillas, Alexandra ; Michell, Danielle L. ; Shihata, Waled A. ; Nicholls, Alyce J. ; Cooney, Olivia D. ; Kraakman, Michael J. ; Veiga, Camilla Bertuzzo ; Jefferis, Ann Maree ; Jackson, Kristy ; Nagareddy, Prabhakara R. ; Lambert, Gavin ; Wong, Connie H.Y. ; Andrews, Karen L. ; Head, Geoff A. ; Chin-Dusting, Jaye ; Murphy, Andrew J. / Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis. In: Haematologica: the hematology journal. 2019 ; Vol. 104, No. 3. pp. 456-467.
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abstract = "Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the b-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.",
author = "Annas Al-Sharea and Lee, {Man K.S.} and Alexandra Whillas and Michell, {Danielle L.} and Shihata, {Waled A.} and Nicholls, {Alyce J.} and Cooney, {Olivia D.} and Kraakman, {Michael J.} and Veiga, {Camilla Bertuzzo} and Jefferis, {Ann Maree} and Kristy Jackson and Nagareddy, {Prabhakara R.} and Gavin Lambert and Wong, {Connie H.Y.} and Andrews, {Karen L.} and Head, {Geoff A.} and Jaye Chin-Dusting and Murphy, {Andrew J.}",
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Al-Sharea, A, Lee, MKS, Whillas, A, Michell, DL, Shihata, WA, Nicholls, AJ, Cooney, OD, Kraakman, MJ, Veiga, CB, Jefferis, AM, Jackson, K, Nagareddy, PR, Lambert, G, Wong, CHY, Andrews, KL, Head, GA, Chin-Dusting, J & Murphy, AJ 2019, 'Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis' Haematologica: the hematology journal, vol. 104, no. 3, pp. 456-467. https://doi.org/10.3324/haematol.2018.192898

Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis. / Al-Sharea, Annas; Lee, Man K.S.; Whillas, Alexandra; Michell, Danielle L.; Shihata, Waled A.; Nicholls, Alyce J.; Cooney, Olivia D.; Kraakman, Michael J.; Veiga, Camilla Bertuzzo; Jefferis, Ann Maree; Jackson, Kristy; Nagareddy, Prabhakara R.; Lambert, Gavin; Wong, Connie H.Y.; Andrews, Karen L.; Head, Geoff A.; Chin-Dusting, Jaye; Murphy, Andrew J.

In: Haematologica: the hematology journal, Vol. 104, No. 3, 28.02.2019, p. 456-467.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis

AU - Al-Sharea, Annas

AU - Lee, Man K.S.

AU - Whillas, Alexandra

AU - Michell, Danielle L.

AU - Shihata, Waled A.

AU - Nicholls, Alyce J.

AU - Cooney, Olivia D.

AU - Kraakman, Michael J.

AU - Veiga, Camilla Bertuzzo

AU - Jefferis, Ann Maree

AU - Jackson, Kristy

AU - Nagareddy, Prabhakara R.

AU - Lambert, Gavin

AU - Wong, Connie H.Y.

AU - Andrews, Karen L.

AU - Head, Geoff A.

AU - Chin-Dusting, Jaye

AU - Murphy, Andrew J.

PY - 2019/2/28

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N2 - Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the b-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.

AB - Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the b-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.

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