TRAIL expression within the pulmonary vascular tissue drives PAH in the Paigen diet–fed ApoE^−/− mouse. (A) TaqMan expression of TRAIL in whole blood from ApoE^−/− and ApoE^−/−/TRAIL^−/− mice using ΔΔCT with 18S rRNA as the endogenous control gene. Four groups of chimeric mice were generated by BMT. ApoE^−/− BM was transplanted into irradiated ApoE^−/−/TRAIL^−/− mice (ApoE^−/− into ApoE^−/−/TRAIL^−/−) to produce chimeras where TRAIL was only expressed within circulating cells, and into ApoE^−/− mice as a positive control for the procedure (ApoE^−/− into ApoE^−/−). Conversely, ApoE^−/−/TRAIL^−/− BM was transplanted into irradiated ApoE^−/− mice (ApoE^−/−/TRAIL^−/− into ApoE^−/−) to generate chimeras where TRAIL was only expressed within the vessel wall, and into ApoE^−/−/TRAIL^−/− (ApoE^−/−/TRAIL^−/− into ApoE^−/−/TRAIL^−/−) mice as a negative control. (B) Western immunoblot for TRAIL in whole lung lysates from representative chimeric mice. (C–F) Bar graphs show RVSP (C), RVEDP (D), LVESP (E), and LVEDP (F), measured in mm Hg. (G–I) Cardiac index (G), ePVRi (H), and RVH (I). (J) Relative percentage of muscularized small pulmonary arteries pulmonary arteries <50 µm in diameter, and the degree of medial wall thickness as a ratio of total vessel size (Media/CSA). (K–M) Pulmonary arteries <50 µm in diameter (K), vessels from 51 to 100 µm in diameter (L), and vessels >100 µm in diameter (M). Error bars represent mean ± SEM, n = 3–6 animals per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001, compared chow-fed equivalent mice unless otherwise stated.