Effect of hypoxia on cell-cell interaction

Research description

Because of their localisation at the interface between blood and tissue, endothelial cells are the first cells to suffer from any modification of the circulation like the decrease in blood flow resulting from blood stasis. Ischemic conditions lead to a decrease in oxygen and nutriment supply to the tissues and the metabolism of endothelial cell seems to be very sensitive to such a situation. Since endothelial cells are ubiquitous and since, by the synthesis of various factors, they modulate the functions of platelets, leukocytes and smooth muscle cells, any alteration for their metabolism can have deleterious consequences for tissue homeostasis.

Our laboratory investigates the mechanisms underlying these processes.

• Hypoxia is able to activate endothelial cells inducing the release of prostaglandins and the synthesis of PAF (platelet-activating factor). This activation occurs due to an increase in the intracellular calcium concentration via the regulation of several ion transporters.
• Hypoxia makes endothelial cells adhesive for neutrophils, through their synthesis of PAF, leading to the adherence and the activation of the neutrophils. Hypoxic endothelial cells also release chemotactic factors for neutrophils.
• Endothelial cells exposed to hypoxia release mitogenic factors for smooth muscle cells. They included prostaglandins and bFGF (basic fibroblast growth factor).
• Perfused human saphenous veins as well as umbilical veins also become adhesive for neutrophils when incubated at low oxygen concentration.
• We proposed a new hypothesis for the appearance of varicose veins, based on these experimental findings. During venous blood stasis, the endothelium creates a pro-inflammatory state which leads to neutrophil infiltration and activation. They will release proteases and oxygen-derived free radicals which can alter the venous wall extracellular matrix. On the other hand, the endothelium also releases mitogens which induce smooth muscle cell dedifferenciation and proliferation. If chronically repeated, these processes can eventually lead to alterations in the venous wall such as the ones actually observed in varicose vein wall.
• Venotropic drugs have been tested on cultured endothelial cells exposed to hypoxia, on perfused human saphenous veins as well as in a double-blind clinical trial using circulating endothelial cells as the following parameter. A strong protective effect was observed in all experimental settings.

A mechanism for this protective effect has been deciphered.