Key result
Hypoxia and extracellular matrix degradation by reactive oxygen species and proteolytic enzymes activate vascular smooth muscle cell proliferation, contributing to vascular remodeling in hypoxic pulmonary hypertension.
Hypoxia-induced extracellular matrix degradation by immune cells promotes vascular smooth muscle cell proliferation, driving vascular remodeling in hypoxic pulmonary hypertension.
ECM oxidation may drive hypoxic PH; leaves open therapeutic targeting pending in vivo and clinical validation.
Pulmonary hypertension is a complex and heterogeneous condition with five main subtypes (groups). This review focuses on pulmonary hypertension caused by chronic hypoxia (hypoxic pulmonary hypertension, HPH, group 3). It is based mainly on our own experimental work, especially our collaboration with the group of Professor Herget, whose fifth anniversary of death we commemorate. We have found that oxidation and degradation of the extracellular matrix (ECM) in vitro, in either the presence or the absence of pro-inflammatory cells, activate vascular smooth muscle cell (VSMC) proliferation. Significant changes in the ECM of pulmonary arteries also occurred in vivo in hypoxic rats, namely a decrease in collagen VI and an increase in matrix metalloproteinase 9 (MMP-9) in the tunica media, which may also contribute to the growth activation of VSMCs. The proliferation of VSMCs was also enhanced in their co-culture with macrophages, most likely due to the paracrine production of growth factors in these cells. However, hypoxia itself has a dual effect: on the one hand, it can activate VSMC proliferation and hyperplasia, but on the other hand, it can also induce VSMC hypertrophy and increased expression of contractile markers in these cells. The influence of hypoxia-inducible factors, microRNAs and galectin-3 in the initiation and development of HPH, and the role of cell types other than VSMCs (endothelial cells, adventitial fibroblasts) are also discussed. Keywords: Vasoconstriction, Remodeling, Oxidation, Degradation, Extracellular matrix, Collagen, Proteolytic enzymes, Metalloproteinases, Macrophages, Mast cells, Smooth muscle cells, Endothelial cells, Fibroblasts, Mesenchymal stem cells, Hypoxia-inducible factor, microRNA, Galectins, Hyperplasia, Hypertrophy, Therapy of hypoxic pulmonary hypertension.
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Bačáková et al. (2024) conducted a review in Hypoxic Pulmonary Hypertension. Hypoxia and extracellular matrix modifications was evaluated. Hypoxia and extracellular matrix degradation by reactive oxygen species and proteolytic enzymes activate vascular smooth muscle cell proliferation, contributing to vascular remodeling in hypoxic pulmonary hypertension.
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