Severe hypoxia drives loss of ST6GAL1-mediated α2,6-sialylation in the epicardial secretome impairing angiogenic activity

The epicardium contributes to cardiac development and regeneration, primarily through paracrine signalling. However, the impact of severe hypoxic stress, such as occurs immediately following myocardial infarction, on the activity of the epicardial secretome remains poorly defined. Here we investigated the angiogenic potential of the epicardial secretome under normoxic and hypoxic conditions. In contrast to expectation, the results demonstrate that the angiogenic effect of epicardial cells on vascular endothelium is hampered under severe hypoxia. Mechanistically, we found that hypoxia-mediated sialylation remodels the epicardial secretome altering its angiogenic potential. Severe hypoxia suppresses St6gal1 gene expression decreasing the level of α2,6-sialylation, as measured by comprehensive lectin profiling and sialyltransferase analysis. Functional studies revealed that both global and α2,6-specific sialylation inhibition markedly compromised the pro-angiogenic capacity of the epicardial secretome, reducing the in vitro tube formation. Our findings indicate that ST6GAL1-dependent α2,6-sialylation is required to activate the pro-angiogenic potential of the epicardial secretome. These data also suggest that glycosylation is a modifiable response to ischemic injury, offering a new therapeutic target for enhancing tissue repair.