Occlusive lung arterial lesions in endothelial-targeted, fas-induced apoptosis transgenic mice

Am J Respir Cell Mol Biol. 2015 Nov;53(5):712-8. doi: 10.1165/rcmb.2014-0311OC.

Abstract

Pulmonary arterial hypertension (PAH) is a lethal disease that is characterized by functional and structural abnormalities involving distal pulmonary arterioles that result in increased pulmonary vascular resistance and ultimately right heart failure. In experimental models of pulmonary hypertension, endothelial cell (EC) apoptosis is a necessary trigger for the development of obliterative lung arteriopathy, inducing the emergence of hyperproliferative and apoptosis-resistant vascular cells. However, it has not been established whether EC apoptosis is sufficient for the induction of complex lung arteriolar lesions. We generated a conditional transgenic system in mice to test the hypothesis that lung endothelial cell apoptosis is sufficient to induce a PAH phenotype. The Fas-induced apoptosis (FIA) construct was expressed under the control of endothelial-specific Tie2 promoter (i.e., EFIA mice), and administration of a small molecule dimerizing agent, AP20187, resulted in modest pulmonary hypertension, which was associated with obliterative vascular lesions localized to distal lung arterioles in a proportion of transgenic mice. These lesions were characterized by proliferating cells, predominantly CD68 macrophages. Although endothelial cell apoptosis was also seen in the kidney, evidence of subsequent arteriopathy was seen only in the lung. This model provides direct evidence that lung endothelial cell apoptosis acts as a trigger to initiate a PAH phenotype and provides initial insight into the potential mechanisms that underlie a lung-specific arterial response to endothelial injury.

Keywords: apoptosis; endothelial cell; pulmonary arterial hypertension; transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Disease Models, Animal*
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism
  • Gene Expression Regulation
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / pathology
  • Lung / drug effects
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Transgenic / genetics*
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Promoter Regions, Genetic
  • Protein Multimerization
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology
  • Signal Transduction
  • Tacrolimus / analogs & derivatives
  • Tacrolimus / pharmacology
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism
  • Transfection
  • fas Receptor / genetics*
  • fas Receptor / metabolism

Substances

  • AP20187
  • Fadd protein, mouse
  • Fas protein, mouse
  • Fas-Associated Death Domain Protein
  • Recombinant Fusion Proteins
  • fas Receptor
  • Receptor, TIE-2
  • Tek protein, mouse
  • Tacrolimus Binding Proteins
  • Tacrolimus