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 (Col1a1R/R) and littermate controls (Col1a1+/+) to hypoxia for 10 days with or without β-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 Col1a1R/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 Col1a1R/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.

Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients

“…Triggers for the vascular remodeling include injury, inflammation, abnormal growth factor expression, and/or exposure to hypoxia (53, 56). Furthermore, disturbances in extracellular matrix (ECM) production, deposition, and composition have been implicated (35,43,46,62), and restoration of ECM balance has been suggested as a strategy to prevent or reverse vascular remodeling processes (8,25).…”

“…Triggers for the vascular remodeling include injury, inflammation, abnormal growth factor expression, and/or exposure to hypoxia (53, 56). Furthermore, disturbances in extracellular matrix (ECM) production, deposition, and composition have been implicated (35,43,46,62), and restoration of ECM balance has been suggested as a strategy to prevent or reverse vascular remodeling processes (8,25).The complex ECM network provides structural support for the cells in the vessel wall, enables intracellular communication, and promotes proliferation, migration, and apoptosis (61). The ECM in human pulmonary vessels predominantly consists of collagen I, elastins, and laminins as well as other ECM components such as fibronectin, tenascin C, and glucosaminoglycans (22).…”

Urotensin II contributes to collagen synthesis and up-regulates Egr-1 expression in cultured pulmonary arterial smooth muscle cells through the ERK1/2 pathway

“…These results indicate that UII could promote PASMC proliferation through the ERK1/2 signaling pathway at the transcript level, and the Egr-1 signaling pathway also was activated. [21]. Collagen is the main component of the extracellular matrix, and it contributes to vascular tension resistance and elasticity [22].…”

Validation of an arterial constitutive model accounting for collagen content and crosslinking

“…Many mechanical testing methods including uniaxial, planar biaxial and pressure-inflation tests have been used to characterize the extrinsic and intrinsic, or more generally, mechanical properties of proximal PAs and their components [1,3,4,6,21–23]. The role of smooth muscle cell activity in proximal PA remodeling, without experimental or pharmacological activation, appears minimal [23,24].…”

“…The role of smooth muscle cell activity in proximal PA remodeling, without experimental or pharmacological activation, appears minimal [23,24]. Instead, changes in the extracellular matrix (e.g., elastin and collagen) can be dramatic.…”