Les Signaux Post Mortem (SPM) de l’apoptose endothéliale : des acteurs du remodelage vasculaire
Immunosuppression regiments improved steadily the incidence of acute rejection with minimal positive effects on chronic rejection.  The latter is characterized by a transplant vasculopathy (TV) similar to native atherosclerosis, accompanied with fibrosis throughout the vascular wall of the allograft.  The pathophysiology associated to TV arose from pionnering work of Russell Ross in 1977.  He proposed the 'Response to Injury' hypothesis revealing that endothelium injury initiated by immunological and non immunological factors favors a vascular repair response through neo-intima thickening at the sites of cellular injury.  However, when endothelial insult is maintained, apoptosis ensues and the vascular repair process perpetuates.  Since inhibition of endothelial apoptosis prevents TV development in vivo, we hypothesized that endothelial apoptosis regulates the vascular repair process through a paracrine program active on the cellular components of the vessel wall.  We have generated an in vitro experimental system to induce endothelial apoptosis in absence of necrosis.  Using a multifunctional and comparative proteomic approach, we have identified 27 post mortem signals (PMS) specifically exported by apoptotic endothelial cells. Some of these PMS display anti-apoptotic function (TCTP and EGF), whereas CTGF was identified as a fibrogenic factor, recapitulating the cellular events associated to the development of TV.  Interestingly, 16 of these SPM did not contain a peptide signal, suggesting that non conventional secretion mechanisms could be favored during the effector phase of apoptosis.  We demonstrated that activated caspase-3 regulates the exosomal secretion pathway associated to the export of nanovesicles TCTP +ve, anti-apoptotic and biochemically different from apoptotic blebs.  Finally, the overall proteomic data  generated a new hypothesis suggesting that in response to apoptotic stress, the cell exports different mediators (soluble and vesicular) by non conventional mechanism through the fusion of endocytic organelles and autophagic vacuoles with the plasma membrane, releasing their content into the extracellular milieu.  This mechanism should be regulated during the effector phase of apoptosis favoring a vascular repair response only when cell’s demise reaches a point of no return.  Therefore, these PMS could be used both as biomarkers of apoptosis or as biopharmaceutical targets to decrease the incidence of chronic vascular repair.
TCTP Transplant vaculopathy apoptosis proteomic nanovesicles non conventional secretion