Tissue factor pathway inhibitor overexpression inhibits hypoxia-induced pulmonary hypertension

Thomas A. White, Tyra A. Witt, Shuchong Pan, Cheryl S. Mueske, Laurel S. Kleppe, Eric W. Holroyd, Hunter C. Champion, Robert D. Simari

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Pulmonary hypertension (PH) is a commonly recognized complication of chronic respiratory disease. Enhanced vasoconstriction, pulmonary vascular remodeling, and in situ thrombosis contribute to the increased pulmonary vascular resistance observed in PH associated with hypoxic lung disease. The tissue factor pathway regulates fibrin deposition in response to acute and chronic vascular injury. We hypothesized that inhibition of the tissue factor pathway wouldresult in attenuation of pathophysiologic parameters typically associated with hypoxia-induced PH. We tested this hypothesis using a chronic hypoxia-induced murine model of PH using mice that overexpress tissue factor pathway inhibitor (TFPI) via the smooth muscle-specific promoter SM22 (TFPI SM22). TFPISM22 mice have increased pulmonary TFPI expression compared with wild-type (WT)mice. InWTmice, exposure to chronic hypoxia (28d at 10% O2) resulted in increased systolic right ventricular and mean pulmonary arterial pressures, changes that were significantly reduced in TFPISM22 mice. Chronic hypoxia also resulted in significant pulmonary vascular muscularization in WT mice, which was significantly reduced in TFPISM22 mice. Given the pleiotropic effects of TFPI, autocrine and paracrine mechanisms for these hemodynamic effects wereconsidered. TFPISM22 micehadless pulmonary fibrin deposition thanWTmice at 3 days after exposure to hypoxia, which is consistent with the antithrombotic effects of TFPI. Additionally, TFPISM22 mice had a significant reduction in the number of proliferating (proliferating cell nuclear antigen positive) pulmonary vascular smooth muscle cells compared withWTmice, which is consistent with in vitro findings. These findings demonstrate that overexpression of TFPI results in improved hemodynamic performance and reduced pulmonary vascular remodeling in a murine model of hypoxia-induced PH. This improvement is in part due to the autocrine and paracrine effects of TFPI overexpression.

Original languageEnglish (US)
Pages (from-to)35-45
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume43
Issue number1
DOIs
StatePublished - Jul 1 2010

Keywords

  • Hypoxia
  • Pulmonary hypertension
  • Tissue factor
  • Tissue factor pathway inhibitor

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Tissue factor pathway inhibitor overexpression inhibits hypoxia-induced pulmonary hypertension'. Together they form a unique fingerprint.

  • Cite this

    White, T. A., Witt, T. A., Pan, S., Mueske, C. S., Kleppe, L. S., Holroyd, E. W., Champion, H. C., & Simari, R. D. (2010). Tissue factor pathway inhibitor overexpression inhibits hypoxia-induced pulmonary hypertension. American journal of respiratory cell and molecular biology, 43(1), 35-45. https://doi.org/10.1165/rcmb.2009-0144OC