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Hypoxic conditions stimulate pulmonary vasoconstriction and vascular remodelling, both pathognomonic changes in pulmonary arterial hypertension (PAH). The secreted protein stromal-derived factor 1α (SDF-1α) is involved in the maintenance of lung homeostasis. New work identified a role for SDF-1α in promoting PAH. Nonetheless, it is largely unknown how hypoxia regulates SDF-1α in the lung and whether this contributes to pathological events during PAH.
In cell and animal experiments, we investigated that hypoxia induces SDF-1α in lungs, pulmonary artery smooth muscle cells and endothelial cells, and pulmonary fibroblasts.
Using a murine model of constitutive hypoxia, we found that hypoxia-mediated induction of pulmonary SDF-1α is a hepatocyte growth factor-dependent process. Additionally, hypoxia-mediated induction of SDF-1α destabilized endothelial cell-cell interactions. This provides genetic evidence that SDF-1α contributes to vascular remodelling during PAH. Expanding cell data to whole tissues, we found that, under hypoxia, pulmonary arteries (PAs) from WT mice had significantly decreased sensitivity to acetylcholine (Ach)-stimulated endothelial-dependent vasodilation. We find in the lungs from individuals with end-stage PAH, both SDF-1αand HGF protein expression increased in the pulmonary vasculature compared with non-PAH controls.
These findings demonstrate that HGF is clearly implicated in the SDF-1α pulmonary regulation and provide new insights on its contribution to PAH-driven vascular remodelling and vasoconstriction.