Effect of Post Covid-19 Hypoxia on Placenta of Normal Pregnant Women: A Possible Role of Hypoxia Inducible Factor-1α.

Hypoxaemia is an ominous sign of COVID-19, and it is usually an indicator of disease severity. An oxygen saturation above 90% is associated with better outcomes. Hypoxia indicates an imbalance of oxygen delivery to tissues and leads to compromised function.

The hypoxia-inducible factors (HIF) are considered master regulators of oxygen homeostasis and are oxygen level sensitive. HIF1a is a heterodimeric transcription factor that bind to hypoxia response elements, which participates through the regulation of the expression of several genes in numerous cellular events such as O2 sensing, glucose metabolism, lipid metabolism, angiogenesis and other aspects of endothelial biology.

PIGF is a proangiogenic protein and member of the vascular endothelial growth factor (VEGF) family. It is one of the key molecules in angiogenesis and vasculogenesis especially during embryogenesis and placental trophoblast is the main source of PIGF throughout the gestational period of pregnancy. It shares structural as well as amino acid sequence similarity with VEGF, but PIGF has binding affinity only for VEGF receptor1(VEGFR-1). The inter-and intramolecular cross-talk between the VEGFR-1 and VEGFR-2 is regulated by PIGF. It binds toVEGFR-1 and displaces VEGF from this receptor, which results in activation and intermolecular trans phosphorylation of VEGFR-2 thereby amplify the VEGF-induced angiogenesis.

Hypoxic environment is essential for the proliferation and differentiation of cytotrophoblast for maintenance of materno-fetal circulation at early periods of pregnancy. But its prevalence in later stages of pregnancy causes several complications that may lead to maternal and fetal morbidity and mortality.

Several researchers have proved that the overexpression of HIF-1α is associated with the increased maternal serum concentration of soluble Fms-like tyrosine kinase 1 (sFlt1) during hypoxic conditions. High circulating levels of sFlt1 exerts an antiangiogenic state that is associated with low levels of proangiogenic factors, such as PIGF, and inhibition of PIGF with its receptor VEGFR-1.