COX-2-derived prostacyclin modulates vascular remodeling

Radu Daniel Rudic, Derek Brinster, Yan Cheng, Susanne Fries, Wen Liang Song, Sandra Austin, Thomas M. Coffman, Garret A. FitzGerald

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Suppression of prostacyclin (PGI2) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase (COX)-2 inhibitors. Herein, we examine if COX-2-derived PGI2 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity. Deletion of the PGI2 receptor (IP) or suppression of PGI2 with the selective COX-2 inhibitor, nimesulide, both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow-induced vascular remodeling. Moreover, nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild-type mice. Generation of both thromboxane (Tx)A2 and the isoprostane, 8, 12 -iso iPF -VI, are increased in the setting of flow reduction and the latter increases further on administration of nimesulide. Deletion of the TxA2 receptor (TP) reduces the hyperplastic response to nimesulide and carotid ligation, despite further augmentation of TP ligand production. Suppression of COX-2-derived PGI2 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress. Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of COX-2.

Original languageEnglish (US)
Pages (from-to)1240-1247
Number of pages8
JournalCirculation research
Volume96
Issue number12
DOIs
StatePublished - Jun 24 2005

Fingerprint

nimesulide
Epoprostenol
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
8-epi-prostaglandin F2alpha
Ligation
Epoprostenol Receptors
Tunica Intima
Thromboxane Receptors
Thromboxane A2
Arteriosclerosis
Common Carotid Artery
Hyperplasia
Atherosclerosis
Theoretical Models
Hemodynamics
Stroke
Myocardial Infarction
Placebos
Vascular Remodeling

Keywords

  • Arteriosclerosis
  • Cyclooxygenase
  • Oxidant stress
  • Prostaglandins
  • Vascular remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Rudic, R. D., Brinster, D., Cheng, Y., Fries, S., Song, W. L., Austin, S., ... FitzGerald, G. A. (2005). COX-2-derived prostacyclin modulates vascular remodeling. Circulation research, 96(12), 1240-1247. https://doi.org/10.1161/01.RES.0000170888.11669.28

COX-2-derived prostacyclin modulates vascular remodeling. / Rudic, Radu Daniel; Brinster, Derek; Cheng, Yan; Fries, Susanne; Song, Wen Liang; Austin, Sandra; Coffman, Thomas M.; FitzGerald, Garret A.

In: Circulation research, Vol. 96, No. 12, 24.06.2005, p. 1240-1247.

Research output: Contribution to journalArticle

Rudic, RD, Brinster, D, Cheng, Y, Fries, S, Song, WL, Austin, S, Coffman, TM & FitzGerald, GA 2005, 'COX-2-derived prostacyclin modulates vascular remodeling', Circulation research, vol. 96, no. 12, pp. 1240-1247. https://doi.org/10.1161/01.RES.0000170888.11669.28
Rudic RD, Brinster D, Cheng Y, Fries S, Song WL, Austin S et al. COX-2-derived prostacyclin modulates vascular remodeling. Circulation research. 2005 Jun 24;96(12):1240-1247. https://doi.org/10.1161/01.RES.0000170888.11669.28
Rudic, Radu Daniel ; Brinster, Derek ; Cheng, Yan ; Fries, Susanne ; Song, Wen Liang ; Austin, Sandra ; Coffman, Thomas M. ; FitzGerald, Garret A. / COX-2-derived prostacyclin modulates vascular remodeling. In: Circulation research. 2005 ; Vol. 96, No. 12. pp. 1240-1247.
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