Endothelial Fate-Mapping in Mice with Pulmonary Hypertension
Background—Pulmonary endothelial injury triggers a reparative program, which in susceptible individuals is characterized by neointima formation, vascular narrowing and the development of pulmonary arterial hypertension. The neointimal cells in human pathologic plexiform lesions frequently coexpress smooth muscle alpha-actin and the endothelial von Willebrand antigen, creating a question about their cellular lineage of origin.
Methods and Results—Experimental pulmonary hypertension with neointima formation develops in C57Bl/6 mice subjected to left pneumonectomy followed one week later by jugular vein injection of monocrotaline pyrrole (20µg/µl)(1µl/g) (Group P/MCTP). Compared to Group Vehicle, by Day 35, Group P/MCTP developed higher right ventricular systolic pressure (54 ± 5 vs. 25 ± 2 mmHg, p < 0.01) and right ventricular hypertrophy (0.58 ± 0.16 vs. 0.26 ± 0.05, p < 0.01). Transgenic Vascular Endothelial-Cadherin (VE-Cad) Cre recombinase or Tie-2 Cre mice were intercrossed with mTomato/mGFP double fluorescent Cre reporter mice to achieve endothelial genetic lineage marking with membrane-targeted GFP. In control mice, few endothelial lineage-marked cells lining the lumen of small pulmonary arteries demonstrate expression of smooth muscle α-actin (SMA). Concurrent with the development of pulmonary hypertension, endothelial lineage-marked cells are prominent in the neointima and exhibit expression of SMA and smooth muscle myosin heavy chain (SM-MHC). Human pulmonary arterial hypertension neointimal lesions contain cells that coexpress endothelial CD31 or von Willebrand antigen, and SMA.
Conclusions—Neointimal cells in pulmonary hypertension include contributions from the endothelial genetic lineage with induced expression of SMA and SM-MHC.
- monocrotaline pyrrole
- genetic lineage marking
- endothelial to mesenchymal transition
- endothelial cell differentiation
- genetically altered mice
- pulmonary circulation
- pulmonary vascular changes
- Received May 21, 2013.
- Revision received October 28, 2013.
- Accepted October 29, 2013.