LAUSR

AIM In heart failure (HF), pulmonary venous hypertension (PVH) produces pulmonary hypertension (PH) with remodeling of pulmonary veins (PV) and arteries (PA). In a porcine PVH model, we performed proteomic-based bioinformatics to investigate unique pathophysiologic mechanisms mediating PA and PV remodeling. METHODS AND RESULTS Large PV were banded (PVH, n = 10) or not (Sham, n = 9) in piglets. At sacrifice, PV and PA were perfusion labeled for vessel specific histology and proteomics. The PA and PV were separately sampled with laser-capture micro-dissection for mass spectrometry.Pulmonary vascular resistance (Wood Units; 8.6 [95% Confidence Interval, 6.3,12.3] versus 2.0 [1.7,2.3]) and PA (19.9 [standard error of mean, 1.1] versus 10.3 [1.1]) and PV (14.2 [1.2] versus 7.6 [1.1]) wall thickness/external diameter (%) were increased in PVH (p < 0.05 for all). Similar numbers of proteins were identified in PA (2093) and PV (2085) with 94% overlap, but biological processes differed. There were more differentially expressed proteins (287 versus 161), altered canonical pathways (17 versus 3) and predicted up-stream regulators (PUSR; 22 versus 6) in PV than PA. In PA and PV, bioinformatics indicated activation of the integrated stress response and mTOR signaling with dysregulated growth. In PV, there was also activation of Rho/Rho kinase signaling with decreased actin cytoskeletal signaling and altered tight and adherens junctions, ephrin B, and caveolae-mediated endocytosis signaling; all indicating disrupted endothelial barrier function. Indeed, protein biomarkers and the top PUSR in PV (TGF-β) suggested endothelial mesenchymal transition (EndoMT) in PV. Findings were similar in human autopsy specimens. CONCLUSION These findings provide new therapeutic targets to oppose pulmonary vascular remodeling in HF-related PH. TRANSLATIONAL PERSPECTIVE In heart failure (HF) related (Group 2) PH, despite remodeling of pulmonary veins (PV) and arteries (PA), therapies targeting PA biology altered in Group 1 PH have not shown consistent benefit. In a porcine Group 2 PH model, microdissection allowed vessel specific (PV and PA) proteomics/bioinformatics. In PA and PV, the integrated stress response and mTOR signaling were activated with evidence of dysregulated growth. In PV, more pathways were altered with broad evidence of disrupted endothelial barrier function and endothelial mesenchymal transition. Findings were confirmed in human specimens and provide new targets for potential therapeutic translation in Group 2 PH.