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.