title: Pulmonary vascular collagen content, not cross-linking, contributes to right ventricular pulsatile afterload and overload in early pulmonary hypertension.
abstract: 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 cross-linking 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 effect of pulmonary vascular collagen content and cross-linking on steady and pulsatile RV afterload and on RV hypertrophy in early HPH. Collagenase-resistant mice (Col1a1R/R) 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 using histological techniques and ELISA in lungs and RVs. In both mouse strains, BAPN did not limit increases in pulmonary arterial pressure or pulmonary vascular resistance, indicating a negligible effect of either collagen content or cross-linking on steady RV afterload. However, BAPN prevented the increase in pulse pressure and RV hypertrophy in Col1a1+/+mice and these effects were absent in Col1a1R/Rmice, suggesting a role for 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 for pulsatile RV afterload in RV overload in early HPH.
  The present study found an important role for collagen content, but not collagen cross-linking, in the pulsatile right ventricular (RV) afterload, which is correlated with RV hypertrophy. These results uncover a new collagen-mediated mechanical mechanism of RV dysfunction in early pulmonary hypertension progression. Furthermore, our results suggest that measures and metrics of pulsatile hemodynamics such as pulse pressure and pulse wave velocity are potentially important to cardiovascular mortality in patients with pulmonary hypertension.
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.|Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado; and.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: David A
authors.initials: DA
authors.lastname: Schreier
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Hinnah
authors.initials: H
authors.lastname: Abid
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin; naomi.chesler@wisc.edu.|Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Chesler
mesh_terms: D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D003094:Collagen / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000378:metabolism / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D063177:Pulse Wave Analysis / Q000379:methods; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D018497:Ventricular Dysfunction, Right / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000629:Aminopropionitrile; D003094:Collagen
keywords: collagen; hypoxic pulmonary hypertension; pulmonary artery remodeling; pulmonary vascular impedance