Hypoxia activates endothelial cells to release inflammatory mediators and growth factors

Summary

Ischemia is a common situation involved in several pathologies. Besides the reperfusion injury which is now well established, ischemia by itself also induces damages. However, the biochemical mechanisms and the cell types involved in these damages are still relatively unknown. We focused our attention on this problem using an in vitro model where human umbilical vein endothelial cells were submitted to a severe hypoxia. We found that before affecting viability, hypoxia is able to strongly activate the endothelial cells. We observed hypoxia induces an increase in the cytosolic calcium concentration, which is then responsible for the activation of phospholipase A₂. Phospholipase A₂ activity releases arachidonic acid which is transformed in endothelial cells into prostaglandins and lyso-PAF which leads to PAF (platelet-activating factor). The synthesis of both PAF and prostaglandins is actually induced by hypoxia.

The physiological consequences of this endothelial cell activation are numerous. First, we found that hypoxia-activated endothelial cells have an increased adhesiveness for neutrophils leading to their activation. Secondly, they release mitogenic molecules for vascular smooth muscle cells identified as PGF_2α and bFGF. These results explain how ischemia by itself can to lead to a local inflammation and induces changes within the vascular wall like its thickening observed in some pathological situations.