Decreased collagen VI in the tunica media of pulmonary vessels during exposure to hypoxia: a novel step in pulmonary arterial remodeling

Abstract

The development of hypoxic pulmonary hypertension is characterized by the structural remodeling of pulmonary arteries. However, the relationship between changes of arterial cells and the extracellular matrix remains unclear. We focused on the evaluation of the non-fibrillar collagen changes in tunica media induced by a four-day exposure to hypoxia and the correlation of these changes with the pulmonary arterial wall structure modifications. We used 20 adult male Wistar rats. The amount and localization of collagen VI, collagen IV, matrix metalloproteinase (MMP) 2, and MMP9 were tested in pulmonary arteries immunohistochemically. Two-dimensional electrophoresis and messenger RNA (mRNA) expression were used for the subsequent comparison of protein changes in arterial tunica media cells (normoxia/hypoxia). Collagen VI was significantly reduced strictly in the tunica media of conduit arteries of hypoxia-exposed rats; however, its mRNA increased. The amount of collagen IV and its mRNA were not altered. We detected a significant increase of MMP9 strictly in the tunica media. In addition, a significantly increased number of MMP9-positive cells surrounded the arteries. MMP2 and the expression of its mRNA were decreased in tunica media. We conclude that the loss of collagen VI is an important step characterizing the remodeling of pulmonary arteries. It could influence the phenotypic status and behavior of smooth muscle cells and modify their proliferation and migration.

The possible role of hypoxia in the affected tissue of relapsed clubfoot

“…It was proven that hypoxia activates MMP2 expression in vascular and retinal endothelial cells 25 . Four-day hypoxia also significantly increased the MMP-9 concentration in smooth muscle cells in pulmonary arteries 26 . The role of MMPs in pulmonary hypoxia has been reviewed in 27 .…”

Mechanisms of Hypoxia-Induced Pulmonary Arterial Stiffening in Mice Revealed by a Functional Genetics Assay of Structural, Functional, and Transcriptomic Data

“…Increased collagen deposition has been speculated to result from chronic hypoxic exposure ( Morrell et al, 1995a , b , 1997 ), though others have suggested that variable degradation and deposition of collagen associates with pulmonary arterial remodeling in animal hypoxia models and humans with pulmonary arterial hypertension ( Zhang et al, 2020 ). Regardless, changes in the extracellular matrix influences changes in SMC phenotype ( Safdar et al, 2014 ; Žaloudíková et al, 2019 ; Chen et al, 2020 ). The need to identify parameters to assess the stiffness of the pulmonary artery has been emphasized further due to the important role that stiffening of the pulmonary artery plays in diseases of the lungs such as pulmonary hypertension and chronic obstructive pulmonary disease ( Sanz et al, 2008 ; Vivodtzev et al, 2013 ; Schäfer et al, 2016 ; Weir-McCall et al, 2018 ).…”

Basement Membrane Remodeling Controls Endothelial Function in Idiopathic Pulmonary Arterial Hypertension

“…Yet so far, research has focused mainly on the class of fibrillar collagens, such as type I or type III collagens secreted predominantly by fibroblasts, pericytes, and activated smooth muscle cells. Indeed, deposition of fibrillar collagens (14,22,23) and associated ECM proteins (24) is found in the neointima, media, and adventitia of remodeled vessels (14,22,23). However, most endothelial cells are not in direct contact with fibrillar collagens but are insulated by the BM, a thin layer of specialized ECM proteins.…”

“…Furthermore, although the BM consists of more than 20 proteins, the ECM comprises more than 200 proteins, 28 of them being collagens. Several other nonlinear collagens, such as collagen VI, can contribute to endothelial cell dysfunction on microvascular and pulmonary arterial level (24). Therefore, to build a clearer picture on the complex role of ECM proteins in the heterogeneous group of lung endothelial cells, future studies are still needed.…”