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Circulation. 2014 Feb 11;129(6):692-703. doi: 10.1161/CIRCULATIONAHA.113.003734. Epub 2013 Nov 7.

Endothelial fate mapping in mice with pulmonary hypertension.

Author information

  • 1Division of Pulmonary and Critical Care Medicine (T.N., L.S., D.S., A.T., P.N.K.) and the Departments of Pathology (G.J.B.) and Anesthesiology (J.R.T., R.G.P.), Stanford University Medical Center, Stanford, CA; and Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China (L.Q.).

Abstract

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 pathological plexiform lesions frequently coexpress smooth muscle α-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 1 week later by jugular vein injection of monocrotaline pyrrole (20 μg/μL and 1 μL/g; group P/MCTP). Compared with the group vehicle, by day 35, group P/MCTP developed higher right ventricular systolic pressure (54±5 versus 25±2 mm Hg; P<0.01) and right ventricular hypertrophy (0.58±0.16 versus 0.26±0.05; P<0.01). Transgenic vascular endothelial-cadherin Cre recombinase or Tie-2 Cre mice were intercrossed with mTomato/mGreen fluorescent protein double-fluorescent Cre reporter mice to achieve endothelial genetic lineage marking with membrane-targeted green fluorescent protein. In control mice, few endothelial lineage-marked cells lining the lumen of small pulmonary arteries demonstrate expression of smooth muscle α-actin. Concurrent with the development of pulmonary hypertension, endothelial lineage-marked cells are prominent in the neointima and exhibit expression of smooth muscle α-actin and smooth muscle myosin heavy chain. Human pulmonary arterial hypertension neointimal lesions contain cells that coexpress endothelial CD31 or von Willebrand antigen and smooth muscle α-actin.

CONCLUSION:

Neointimal cells in pulmonary hypertension include contributions from the endothelial genetic lineage with induced expression of smooth muscle α-actin and smooth muscle myosin heavy chain.

KEYWORDS:

cell lineage; monocrotaline pyrrole; pneumonectomy; vascular diseases

PMID:
24201301
[PubMed - indexed for MEDLINE]
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