Effects of collagen deposition on passive and active mechanical properties of large pulmonary arteries in hypoxic pulmonary hypertension

Abstract

Proximal pulmonary artery (PA) stiffening is a strong predictor of mortality in pulmonary hypertension. Collagen accumulation is mainly responsible for PA stiffening in hypoxia-induced pulmonary hypertension (HPH) in mouse models. We hypothesized that collagen cross-linking and the type I isoform are the main determinants of large PA mechanical changes during HPH, which we tested by exposing mice that resist type I collagen degradation (Col1a1$^\mathrm{R/R})$ and littermate controls (Col1a1$^{+/+})$ to hypoxia for 10 days with or without $\beta$-aminopropionitrile (BAPN) treatment to prevent cross-link formation. Static and dynamic mechanical tests were performed on isolated PAs with smooth muscle cells (SMC) in passive and active states. Percentages of type I and III collagen were quantified by histology; total collagen content and cross-linking were measured biochemically. In the SMC passive state, for both genotypes, hypoxia tended to increase PA stiffness and damping capacity, and BAPN treatment limited these increases. These changes were correlated with collagen cross-linking ($p<0.05$). In the SMC active state, hypoxia increased PA dynamic stiffness and BAPN had no effect in Col1a1$^{+/+}$ mice ($p<0.05$). PA stiffness did not change in Col1a1$^\mathrm{R/R}$ mice. Similarly, damping capacity did not change for either genotype. Type I collagen accumulated more in Col1a1$^{+/+}$ mice, whereas type III collagen increased more in Col1a1$^\mathrm{R/R}$ mice during HPH. In summary, PA passive mechanical properties (both static and dynamic) are related to collagen cross-linking. Type I collagen turnover is critical to large PA remodeling during HPH when collagen metabolism is not mutated and type III collagen may serve as a reserve.