Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow

Stephen Matthew Black, Eugenia Mata-Greenwood, Robert W. Dettman, Boaz Ovadia, Robert K. Fitzgerald, Olaf Reinhartz, Stefan Thelitz, Robin H. Steinhorn, Rene Gerrets, Karen Hendricks-Munoz, Gregory A. Ross, Janine M. Bekker, Michael J. Johengen, Jeffrey R. Fineman

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Background - Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Methods and Results - Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2 ± 113.8, versus 209.8 ± 61.8 pg/g, P<0.05). In shunt lambs (n = 9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ET A receptor antagonist PD 156707 (n = 3). This pulmonary vasoconstriction was mimicked by exogenous Ala 1,3,11,15 ET-1 (4 Ala ET-1), the ET B receptor agonist, and was blocked by the ET B receptor antagonist BQ 788 (n = 3). However, in control lambs (n = 7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ET B receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Conclusions - Over time, increased pulmonary blood flow and/or pressure results in the emergence of ET B -mediated vasoconstriction, which coincides with the emergence of ET B receptors on smooth muscle cells. These data suggest an important role for ET B receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

Original languageEnglish (US)
Pages (from-to)1646-1654
Number of pages9
JournalCirculation
Volume108
Issue number13
DOIs
StatePublished - Sep 30 2003

Fingerprint

Pulmonary Heart Disease
Endothelins
Vasoconstriction
Smooth Muscle Myocytes
Endothelin-1
Lung
Pulmonary Hypertension
Blood Vessels
Animal Models
Immunohistochemistry
Transplants
Pressure

Keywords

  • Endothelin
  • Heart defects, congenital
  • Pulmonary heart disease

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Black, S. M., Mata-Greenwood, E., Dettman, R. W., Ovadia, B., Fitzgerald, R. K., Reinhartz, O., ... Fineman, J. R. (2003). Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow. Circulation, 108(13), 1646-1654. https://doi.org/10.1161/01.CIR.0000087596.01416.2F

Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow. / Black, Stephen Matthew; Mata-Greenwood, Eugenia; Dettman, Robert W.; Ovadia, Boaz; Fitzgerald, Robert K.; Reinhartz, Olaf; Thelitz, Stefan; Steinhorn, Robin H.; Gerrets, Rene; Hendricks-Munoz, Karen; Ross, Gregory A.; Bekker, Janine M.; Johengen, Michael J.; Fineman, Jeffrey R.

In: Circulation, Vol. 108, No. 13, 30.09.2003, p. 1646-1654.

Research output: Contribution to journalArticle

Black, SM, Mata-Greenwood, E, Dettman, RW, Ovadia, B, Fitzgerald, RK, Reinhartz, O, Thelitz, S, Steinhorn, RH, Gerrets, R, Hendricks-Munoz, K, Ross, GA, Bekker, JM, Johengen, MJ & Fineman, JR 2003, 'Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow', Circulation, vol. 108, no. 13, pp. 1646-1654. https://doi.org/10.1161/01.CIR.0000087596.01416.2F
Black, Stephen Matthew ; Mata-Greenwood, Eugenia ; Dettman, Robert W. ; Ovadia, Boaz ; Fitzgerald, Robert K. ; Reinhartz, Olaf ; Thelitz, Stefan ; Steinhorn, Robin H. ; Gerrets, Rene ; Hendricks-Munoz, Karen ; Ross, Gregory A. ; Bekker, Janine M. ; Johengen, Michael J. ; Fineman, Jeffrey R. / Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow. In: Circulation. 2003 ; Vol. 108, No. 13. pp. 1646-1654.
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abstract = "Background - Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Methods and Results - Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2 ± 113.8, versus 209.8 ± 61.8 pg/g, P<0.05). In shunt lambs (n = 9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ET A receptor antagonist PD 156707 (n = 3). This pulmonary vasoconstriction was mimicked by exogenous Ala 1,3,11,15 ET-1 (4 Ala ET-1), the ET B receptor agonist, and was blocked by the ET B receptor antagonist BQ 788 (n = 3). However, in control lambs (n = 7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ET B receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Conclusions - Over time, increased pulmonary blood flow and/or pressure results in the emergence of ET B -mediated vasoconstriction, which coincides with the emergence of ET B receptors on smooth muscle cells. These data suggest an important role for ET B receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.",
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AU - Black, Stephen Matthew

AU - Mata-Greenwood, Eugenia

AU - Dettman, Robert W.

AU - Ovadia, Boaz

AU - Fitzgerald, Robert K.

AU - Reinhartz, Olaf

AU - Thelitz, Stefan

AU - Steinhorn, Robin H.

AU - Gerrets, Rene

AU - Hendricks-Munoz, Karen

AU - Ross, Gregory A.

AU - Bekker, Janine M.

AU - Johengen, Michael J.

AU - Fineman, Jeffrey R.

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N2 - Background - Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Methods and Results - Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2 ± 113.8, versus 209.8 ± 61.8 pg/g, P<0.05). In shunt lambs (n = 9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ET A receptor antagonist PD 156707 (n = 3). This pulmonary vasoconstriction was mimicked by exogenous Ala 1,3,11,15 ET-1 (4 Ala ET-1), the ET B receptor agonist, and was blocked by the ET B receptor antagonist BQ 788 (n = 3). However, in control lambs (n = 7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ET B receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Conclusions - Over time, increased pulmonary blood flow and/or pressure results in the emergence of ET B -mediated vasoconstriction, which coincides with the emergence of ET B receptors on smooth muscle cells. These data suggest an important role for ET B receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

AB - Background - Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Methods and Results - Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2 ± 113.8, versus 209.8 ± 61.8 pg/g, P<0.05). In shunt lambs (n = 9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ET A receptor antagonist PD 156707 (n = 3). This pulmonary vasoconstriction was mimicked by exogenous Ala 1,3,11,15 ET-1 (4 Ala ET-1), the ET B receptor agonist, and was blocked by the ET B receptor antagonist BQ 788 (n = 3). However, in control lambs (n = 7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ET B receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Conclusions - Over time, increased pulmonary blood flow and/or pressure results in the emergence of ET B -mediated vasoconstriction, which coincides with the emergence of ET B receptors on smooth muscle cells. These data suggest an important role for ET B receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

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