04 February 2019 by Bradley Wertheim

Early RV-PA uncoupling is associated with a distinct pulmonary endothelial transcriptomic phenotype in experimental pulmonary arterial hypertension in vivo

Identifying pulmonary arterial hypertension (PAH) early in the disease course may be important for improving clinical outcomes. However, the right heart physiology and pulmonary microvascular endothelial cell (PMVEC) biological profile of early PAH is incompletely characterized. We hypothesized that early PAH is defined by right ventricular-pulmonary arterial (RV-PA) uncoupling that corresponds to a unique PMVEC transcriptional profile. To test this hypothesis, Sprague Dawley rats were administered monocrotaline (MCT) (60 mg/kg, day 0) by intraperitoneal injection, and RV pressure-volume loops were acquired invasively at various timepoints. MCT rats at day 23 had elevated pulmonary artery systolic pressure (PASP) (25.2 ± 1.2 vs. 67.4 ± 8.3 mmHg, P=0.005), indexed pulmonary vascular resistance (PVRi) (50 ± 8 vs 729 ± 190 mmHg*min*g/mL, P=0.005), and RV-PA uncoupling (1.13 ± 0.05 vs. 0.68 ± 0.04, RV end-systolic elastance/pulmonary arterial elastance [Ees/Ea], P<0.001) compared to control.  However, RV-PA uncoupling was also observed at day 15 vs. control (1.13 ± 0.05 vs. 0.90 ± 0.06, Ees/Ea, P=0.02), which was associated with increased PVRi (50 ± 8 vs. 213 ± 29 mmHg*min*g-1*mL-1, P<0.001) without pulmonary hypertension (25 ± 1.2 vs. 33.2 ± 2.7 mmHg, PASP, P=0.02). Next, high quality mRNA (RIN >8.3) was isolated from control, early PAH (day 15), and PAH (day 23) PMVECs, and analyzed by RNASEQ next-generation sequencing using a novel method that does not require cell expansion in vitro (N=6 rats/condition). A greater number of unique differentially expressed genes (FDR<0.05) were observed for control vs. early PAH compared to early PAH vs. PAH (3815 vs. 39 genes). These data suggest that early PAH is characterized by RV-PA uncoupling and a distinct PMVEC transcriptomic profile that precedes severe pulmonary hypertension. Determining the mechanistic implications of these data may offer important insight into the pathobiology of early PAH and novel treatment targets.

About the author

profile picture of Bradley Wertheim

Bradley Wertheim

Fellow in pulmonary and critical care medicine

Brigham and Women's Hospital

United States

Key Contributors

Bradley M. Wertheim, Yi-Dong Lin, Ruisheng Wang, Ying-Yi Zhang, Andriy O. Samokhin, George A. Alba, Elena Arons, Todd M. Kolb, Ryan J. Tedford, Paul B. Yu, and Bradley A. Maron.

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