FIGURE 7.

The mechanisms leading to the onset of hypoxic human amniotic fluid‐derived stem cell (hAFS) secretome‐induced intracellular Ca²⁺ oscillations in endothelial colony‐forming cells (ECFCs). Exposure of circulating ECFCs to hypoxic hAFS secretome (hAFS‐CM^Hypo) results in phospholipase C (PLC) engagement, followed by production of diacylglycerol (DAG) and inositol‐1,4,5‐trisphosphate (InsP₃). DAG is converted by DAG lipase into arachidonic acid (AA), which gates transient receptor potential vanilloid 4 (TRPV4) to mediate extracellular Ca²⁺ entry through the plasma membrane. InsP₃ primes ER‐embedded to be activated by the incoming Ca²⁺. Nicotinic acid adenine dinucleotide phosphate (NAADP)‐induced endolysosomal (EL) Ca²⁺ release mediated by two‐pore channel 1 (TPC1) is also likely to contribute to the Ca²⁺‐dependent recruitment of InsP₃ receptors (InsP₃Rs). Endoplasmic reticulum (ER) Ca²⁺ depletion, in turn, leads to store‐operated Ca²⁺ entry (SOCE) activation and maintenance of intracellular Ca²⁺ oscillations over time (not shown)