Pulmonary vascular collagen content, not cross-linking, contributes to right ventricular pulsatile afterload and overload in early pulmonary hypertension.

Hypoxic pulmonary hypertension (HPH) is associated with pulmonary artery (PA) remodeling and right ventricular (RV) overload. We have previously uncovered collagen-mediated mechanisms of proximal PA stiffening in early HPH by manipulating collagen degradation and crosslinking using a transgenic mouse strain and a potent collagen cross-link inhibitor β-aminopropionitrile (BAPN). However, the roles of collagen in distal PA remodeling, overall RV afterload and RV hypertrophy in HPH remain unknown. Here, we used the same experimental strategy to investigate the impact of pulmonary vascular collagen content and cross-linking on steady and pulsatile RV afterload as well as RV hypertrophy in early HPH. Collagenase-resistant mice (Col1a1) and their littermate controls (Col1a1) were exposed to normobaric hypoxia for 10 days with or without BAPN treatment. In vivo pulmonary vascular impedance, a comprehensive measure of RV afterload, was measured via simultaneous RV catheterization and echocardiography. Morphology and collagen accumulation were examined by histology and ELISA in lungs and RVs. In both mouse strains, BAPN did not limit increases in pulmonary arterial pressure or pulmonary vascular resistance, indicating negligible effect of either collagen content or crosslinking on steady RV afterload. However, BAPN prevented the increase in pulse pressure and RV hypertrophy in the Col1a1 mice and these effects were absent in the Col1a1, suggesting a role of PA collagen content, not cross-linking, in the pulsatile RV afterload. Moreover, we found a significant correlation between pulse pressure and RV hypertrophy, indicating an important role of pulsatile RV afterload in RV overload in early HPH.