Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway

Anthony R. White, Sungwoo Ryoo, Lukasz Bugaj, David O. Attarzadeh, Srikanth Thiyagarajan, Kexun Chen, Sarah Attwater, Bryce Abbot, Dechun Li, Hunter C. Champion, Artin A. Shoukas, Daniel Nyhan, Joshua Hare, Dan E. Berkowitz, Eric C. Tuday

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Emerging evidence suggests that nitric oxide (NO) plays a pivotal role in the mechanism of vascular hyporesponsiveness contributing to microgravity-induced orthostatic intolerance. The cellular and enzymatic source of the NO, however, remains controversial. In addition, the time course of the endothelial-dependent contribution remains unstudied. We tested the hypotheses that the change in vasoresponsiveness seen in acute (3-day) hindlimb unweighted (HLU) animals is due to an endothelium-dependent mechanism and that endothelial-dependent attenuation in vasoreactivity is due to endothelial nitric oxide synthase (NOS-3) dependent activation. Vasoreactivity was investigated in rat aortic rings following acute HLU treatment. Dose responsiveness to norepinepherine (NE) was depressed after 3-day HLU [1,338 ± 54 vs. 2,325 ± 58 mg at max (NE), HLU vs. C, P < 0.001]. However, removal of the endothelium restored the vascular contractility to that of C. In addition, 1H-oxadiazole quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, restored the reduced vasoconstrictor responses to phenylephrine (PE) seen in 3-day HLU rings (1.30 ± 0.10 vs. 0.53 ± 0.07 g, HLU + ODQ vs. HLU, P = 0.0001). Ca+ dependent nitric oxide synthase (NOS) activity was increased, as was vascular NO products as a result of HLU. While NOS-3 expression was not increased in HLU rats, phosphorylation of NOS-3 at serine-1177 (an activator of NOS-3) was increased while phosphorylation of serine-495 (an inactivator of NOS-3) was decreased. These findings demonstrate that changes in vasoresponsiveness in the acute HLU model of microgravity are due to an upregulation of the endothelial-dependent NO/cGMP pathway through NOS phosphorylation.

Original languageEnglish
Pages (from-to)395-404
Number of pages10
JournalEuropean Journal of Applied Physiology
Volume110
Issue number2
DOIs
StatePublished - Sep 1 2010

Fingerprint

Weightlessness
Hindlimb
Endothelium
Nitric Oxide
Up-Regulation
Nitric Oxide Synthase
Oxadiazoles
Quinoxalines
Phosphorylation
Serine
Blood Vessels
Orthostatic Intolerance
Nitric Oxide Synthase Type III
Vascular Endothelium
Phenylephrine
Vasoconstrictor Agents

Keywords

  • Aorta
  • Endothelium
  • Hindlimb unweighting
  • Microgravity
  • Vascular

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Orthopedics and Sports Medicine
  • Physiology (medical)

Cite this

Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway. / White, Anthony R.; Ryoo, Sungwoo; Bugaj, Lukasz; Attarzadeh, David O.; Thiyagarajan, Srikanth; Chen, Kexun; Attwater, Sarah; Abbot, Bryce; Li, Dechun; Champion, Hunter C.; Shoukas, Artin A.; Nyhan, Daniel; Hare, Joshua; Berkowitz, Dan E.; Tuday, Eric C.

In: European Journal of Applied Physiology, Vol. 110, No. 2, 01.09.2010, p. 395-404.

Research output: Contribution to journalArticle

White, AR, Ryoo, S, Bugaj, L, Attarzadeh, DO, Thiyagarajan, S, Chen, K, Attwater, S, Abbot, B, Li, D, Champion, HC, Shoukas, AA, Nyhan, D, Hare, J, Berkowitz, DE & Tuday, EC 2010, 'Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway', European Journal of Applied Physiology, vol. 110, no. 2, pp. 395-404. https://doi.org/10.1007/s00421-010-1514-7
White, Anthony R. ; Ryoo, Sungwoo ; Bugaj, Lukasz ; Attarzadeh, David O. ; Thiyagarajan, Srikanth ; Chen, Kexun ; Attwater, Sarah ; Abbot, Bryce ; Li, Dechun ; Champion, Hunter C. ; Shoukas, Artin A. ; Nyhan, Daniel ; Hare, Joshua ; Berkowitz, Dan E. ; Tuday, Eric C. / Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway. In: European Journal of Applied Physiology. 2010 ; Vol. 110, No. 2. pp. 395-404.
@article{ce9be68249ef48c687df9eb7060ec757,
title = "Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway",
abstract = "Emerging evidence suggests that nitric oxide (NO) plays a pivotal role in the mechanism of vascular hyporesponsiveness contributing to microgravity-induced orthostatic intolerance. The cellular and enzymatic source of the NO, however, remains controversial. In addition, the time course of the endothelial-dependent contribution remains unstudied. We tested the hypotheses that the change in vasoresponsiveness seen in acute (3-day) hindlimb unweighted (HLU) animals is due to an endothelium-dependent mechanism and that endothelial-dependent attenuation in vasoreactivity is due to endothelial nitric oxide synthase (NOS-3) dependent activation. Vasoreactivity was investigated in rat aortic rings following acute HLU treatment. Dose responsiveness to norepinepherine (NE) was depressed after 3-day HLU [1,338 ± 54 vs. 2,325 ± 58 mg at max (NE), HLU vs. C, P < 0.001]. However, removal of the endothelium restored the vascular contractility to that of C. In addition, 1H-oxadiazole quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, restored the reduced vasoconstrictor responses to phenylephrine (PE) seen in 3-day HLU rings (1.30 ± 0.10 vs. 0.53 ± 0.07 g, HLU + ODQ vs. HLU, P = 0.0001). Ca+ dependent nitric oxide synthase (NOS) activity was increased, as was vascular NO products as a result of HLU. While NOS-3 expression was not increased in HLU rats, phosphorylation of NOS-3 at serine-1177 (an activator of NOS-3) was increased while phosphorylation of serine-495 (an inactivator of NOS-3) was decreased. These findings demonstrate that changes in vasoresponsiveness in the acute HLU model of microgravity are due to an upregulation of the endothelial-dependent NO/cGMP pathway through NOS phosphorylation.",
keywords = "Aorta, Endothelium, Hindlimb unweighting, Microgravity, Vascular",
author = "White, {Anthony R.} and Sungwoo Ryoo and Lukasz Bugaj and Attarzadeh, {David O.} and Srikanth Thiyagarajan and Kexun Chen and Sarah Attwater and Bryce Abbot and Dechun Li and Champion, {Hunter C.} and Shoukas, {Artin A.} and Daniel Nyhan and Joshua Hare and Berkowitz, {Dan E.} and Tuday, {Eric C.}",
year = "2010",
month = "9",
day = "1",
doi = "10.1007/s00421-010-1514-7",
language = "English",
volume = "110",
pages = "395--404",
journal = "European Journal of Applied Physiology",
issn = "1439-6319",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway

AU - White, Anthony R.

AU - Ryoo, Sungwoo

AU - Bugaj, Lukasz

AU - Attarzadeh, David O.

AU - Thiyagarajan, Srikanth

AU - Chen, Kexun

AU - Attwater, Sarah

AU - Abbot, Bryce

AU - Li, Dechun

AU - Champion, Hunter C.

AU - Shoukas, Artin A.

AU - Nyhan, Daniel

AU - Hare, Joshua

AU - Berkowitz, Dan E.

AU - Tuday, Eric C.

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Emerging evidence suggests that nitric oxide (NO) plays a pivotal role in the mechanism of vascular hyporesponsiveness contributing to microgravity-induced orthostatic intolerance. The cellular and enzymatic source of the NO, however, remains controversial. In addition, the time course of the endothelial-dependent contribution remains unstudied. We tested the hypotheses that the change in vasoresponsiveness seen in acute (3-day) hindlimb unweighted (HLU) animals is due to an endothelium-dependent mechanism and that endothelial-dependent attenuation in vasoreactivity is due to endothelial nitric oxide synthase (NOS-3) dependent activation. Vasoreactivity was investigated in rat aortic rings following acute HLU treatment. Dose responsiveness to norepinepherine (NE) was depressed after 3-day HLU [1,338 ± 54 vs. 2,325 ± 58 mg at max (NE), HLU vs. C, P < 0.001]. However, removal of the endothelium restored the vascular contractility to that of C. In addition, 1H-oxadiazole quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, restored the reduced vasoconstrictor responses to phenylephrine (PE) seen in 3-day HLU rings (1.30 ± 0.10 vs. 0.53 ± 0.07 g, HLU + ODQ vs. HLU, P = 0.0001). Ca+ dependent nitric oxide synthase (NOS) activity was increased, as was vascular NO products as a result of HLU. While NOS-3 expression was not increased in HLU rats, phosphorylation of NOS-3 at serine-1177 (an activator of NOS-3) was increased while phosphorylation of serine-495 (an inactivator of NOS-3) was decreased. These findings demonstrate that changes in vasoresponsiveness in the acute HLU model of microgravity are due to an upregulation of the endothelial-dependent NO/cGMP pathway through NOS phosphorylation.

AB - Emerging evidence suggests that nitric oxide (NO) plays a pivotal role in the mechanism of vascular hyporesponsiveness contributing to microgravity-induced orthostatic intolerance. The cellular and enzymatic source of the NO, however, remains controversial. In addition, the time course of the endothelial-dependent contribution remains unstudied. We tested the hypotheses that the change in vasoresponsiveness seen in acute (3-day) hindlimb unweighted (HLU) animals is due to an endothelium-dependent mechanism and that endothelial-dependent attenuation in vasoreactivity is due to endothelial nitric oxide synthase (NOS-3) dependent activation. Vasoreactivity was investigated in rat aortic rings following acute HLU treatment. Dose responsiveness to norepinepherine (NE) was depressed after 3-day HLU [1,338 ± 54 vs. 2,325 ± 58 mg at max (NE), HLU vs. C, P < 0.001]. However, removal of the endothelium restored the vascular contractility to that of C. In addition, 1H-oxadiazole quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, restored the reduced vasoconstrictor responses to phenylephrine (PE) seen in 3-day HLU rings (1.30 ± 0.10 vs. 0.53 ± 0.07 g, HLU + ODQ vs. HLU, P = 0.0001). Ca+ dependent nitric oxide synthase (NOS) activity was increased, as was vascular NO products as a result of HLU. While NOS-3 expression was not increased in HLU rats, phosphorylation of NOS-3 at serine-1177 (an activator of NOS-3) was increased while phosphorylation of serine-495 (an inactivator of NOS-3) was decreased. These findings demonstrate that changes in vasoresponsiveness in the acute HLU model of microgravity are due to an upregulation of the endothelial-dependent NO/cGMP pathway through NOS phosphorylation.

KW - Aorta

KW - Endothelium

KW - Hindlimb unweighting

KW - Microgravity

KW - Vascular

UR - http://www.scopus.com/inward/record.url?scp=77956617696&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956617696&partnerID=8YFLogxK

U2 - 10.1007/s00421-010-1514-7

DO - 10.1007/s00421-010-1514-7

M3 - Article

VL - 110

SP - 395

EP - 404

JO - European Journal of Applied Physiology

JF - European Journal of Applied Physiology

SN - 1439-6319

IS - 2

ER -