Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells

Laura E. Fredenburgh, Olin D. Liang, Alvaro A. Macias, Thomas R. Polte, Xiaoli Liu, Dario F. Riascos, Su Wol Chung, Scott L. Schissel, Donald E. Ingber, S. Alex Mitsialis, Stella Kourembanas, Mark A. Perrella

Research output: Contribution to journalArticle

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Abstract

BACKGROUND - Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia. METHODS AND RESULTS - To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ETA) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ETA receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I2 analog, and prostaglandin E2 abrogated the potent contractile response to hypoxia and restored the wild-type phenotype. CONCLUSIONS - Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ETA receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I2 or prostaglandin E2.

Original languageEnglish (US)
Pages (from-to)2114-2122
Number of pages9
JournalCirculation
Volume117
Issue number16
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

Fingerprint

Cyclooxygenase 2
Vascular Smooth Muscle
Pulmonary Hypertension
Smooth Muscle Myocytes
Pulmonary Artery
Lung
Hypertrophy
Cell Hypoxia
Epoprostenol
Dinoprostone
Blood Vessels
Hypoxia
Iloprost
Right Ventricular Hypertrophy
Synthetic Prostaglandins
Endothelin A Receptors
Traction
Arterioles
Ventricular Pressure
Extracellular Matrix

Keywords

  • Hypertension, pulmonary
  • Hypertrophy
  • Hypoxia
  • Prostaglandins
  • Remodeling
  • Vasculature

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. / Fredenburgh, Laura E.; Liang, Olin D.; Macias, Alvaro A.; Polte, Thomas R.; Liu, Xiaoli; Riascos, Dario F.; Chung, Su Wol; Schissel, Scott L.; Ingber, Donald E.; Mitsialis, S. Alex; Kourembanas, Stella; Perrella, Mark A.

In: Circulation, Vol. 117, No. 16, 01.04.2008, p. 2114-2122.

Research output: Contribution to journalArticle

Fredenburgh, LE, Liang, OD, Macias, AA, Polte, TR, Liu, X, Riascos, DF, Chung, SW, Schissel, SL, Ingber, DE, Mitsialis, SA, Kourembanas, S & Perrella, MA 2008, 'Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells', Circulation, vol. 117, no. 16, pp. 2114-2122. https://doi.org/10.1161/CIRCULATIONAHA.107.716241
Fredenburgh, Laura E. ; Liang, Olin D. ; Macias, Alvaro A. ; Polte, Thomas R. ; Liu, Xiaoli ; Riascos, Dario F. ; Chung, Su Wol ; Schissel, Scott L. ; Ingber, Donald E. ; Mitsialis, S. Alex ; Kourembanas, Stella ; Perrella, Mark A. / Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. In: Circulation. 2008 ; Vol. 117, No. 16. pp. 2114-2122.
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abstract = "BACKGROUND - Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia. METHODS AND RESULTS - To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ETA) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ETA receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I2 analog, and prostaglandin E2 abrogated the potent contractile response to hypoxia and restored the wild-type phenotype. CONCLUSIONS - Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ETA receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I2 or prostaglandin E2.",
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T1 - Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells

AU - Fredenburgh, Laura E.

AU - Liang, Olin D.

AU - Macias, Alvaro A.

AU - Polte, Thomas R.

AU - Liu, Xiaoli

AU - Riascos, Dario F.

AU - Chung, Su Wol

AU - Schissel, Scott L.

AU - Ingber, Donald E.

AU - Mitsialis, S. Alex

AU - Kourembanas, Stella

AU - Perrella, Mark A.

PY - 2008/4/1

Y1 - 2008/4/1

N2 - BACKGROUND - Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia. METHODS AND RESULTS - To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ETA) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ETA receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I2 analog, and prostaglandin E2 abrogated the potent contractile response to hypoxia and restored the wild-type phenotype. CONCLUSIONS - Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ETA receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I2 or prostaglandin E2.

AB - BACKGROUND - Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia. METHODS AND RESULTS - To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ETA) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ETA receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I2 analog, and prostaglandin E2 abrogated the potent contractile response to hypoxia and restored the wild-type phenotype. CONCLUSIONS - Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ETA receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I2 or prostaglandin E2.

KW - Hypertension, pulmonary

KW - Hypertrophy

KW - Hypoxia

KW - Prostaglandins

KW - Remodeling

KW - Vasculature

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