15 February 2020 by Rafael Soares Godoy

Of mice and rats – profound species differences in the capacity for lung microvascular repair after widespread lung endothelial injury and apoptosis

Introduction: We studied mechanisms of lung microvasculature repair in two models of endothelial cell (EC) injury: a murine transgenic model for the diphtheria toxin (DT) mediated
ablation of ECs and a rat model treated with the VEGFR2 inhibitor, SU5416 (SU).

Results: After a single dose of 10ng DT, transgenic mice expressing the human DT receptor targeted to ECs showed an increase in activated caspase 3 and TUNEL labeling in lung ECs at 48 and 72 hours post treatment compared to saline controls, resulting in a 78±10% (p<0.001) decrease CD144+ lung ECs by flow cytometry. This was associated with a 35±8% decrease in total lung arterial volume assessed by Micro-CT, mainly in the microcirculation (vessels between 50-150 um in diameter). Right ventricular systolic pressure (RVSP) was increased at 72 hours in DT vs. saline treated DTR mice (RVSP: 34±1 vs. 24±0.35 mmHg, respectively p<0.0001,
n=19), whereas right ventricular hypertrophy (RVH n=15) was only seen at 1 week (0.27±0.006 vs. 0.24±0.004; respectively; p=0.001). Remarkably, there was a full recovery in EC number and microvascular volume by one week after DT treatment, with normalization of RVSP and lung morphology, consistent with efficient microvascular repair. Rats treated with a single injection SU5416 (20 mg/kg) showed a similar increase in RVSP at 1-week (39±5 mmHg vs 28±4 mmHg, SU and Control respectively, n=9, p=0.001) and a ~40% reduction in total lung arterial volume by Micro-CT (6.1 e11±9.1 e10 vs. 3.8e11±2.5e10 μm3, p=0.001). However, in contrast to mice, rats did not show any significant recovery at 3- or 5-weeks following SU administration for RVSP (39±2 mmHg and 40±2 mmHg, respectively) or microvascular loss (4.5e11±4e10 and 4.6e11±4e10 μm3, NS vs. 1-week 3.8e11±2.5e10 μm3).

Conclusions: The capacity for lung microvasculature repair was markedly greater in mice vs. rats, possibly contributing to differences in susceptibility to PAH induced by EC injury.

Key Contributors

Rafael Soares Godoy, Mohammed Taha, Yupu Deng, Katelynn Rowe, Nicholas Cober, Duncan J Stewart Sinclair Center for Regenerative Medicine, Ottawa Hospital Research Institute, Canada University of Ottawa, Faculty of Medicine, Ottawa, Canada


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