P53 depletion promotes neovascularization and brain repair after intracerebral hemorrhage

Resumen del trabajo presentado en el 19 Congreso Nacional de la SENC celebrado en Lleida del 3 al 5 de noviembre de 2021Brain neovascularization has been associated with good prognosis of intracerebral hemorrhage (ICH) patients. We previously showed that the human Tp53 Arg72Pro SNP modulates brain endothelial cells survival after ICH, which is essential for the secretion of growth factors and cytokines (i.e. VEGF) that mediate the mobilization of endothelial progenitor cells (EPCs) from the bone marrow to the peripheral blood. EPCs promote brain vascular repair after ICH. Then, pro-apoptotic p53 would be a negative regulator of EPC mobilization, thus affecting the functional outcome after ICH. Since p53 is accumulated in the brain after ICH, we speculate that p53 destabilization not only will promote cell survival, but also vascular recovery and brain repair. p53 KO mice were subjected to an experimental model of ICH in vivo by injecting bacterial collagenase into the basal ganglia. Proliferative markers (BrdU, Ki67) and perfusion status of newly-formed blood vessels in the brain was also analyzed after Evans blue injection. We observed that p53 loss reduced lesion volume and significantly boost levels of circulating EPCs in mice from 72 hours after ICH. Knockdown of p53 also increased proliferative events in SVZ and lesion areas, as evidenced by BrdU incorporation and Ki67 staining. Consequently, an improved vascular repair response was achieved in p53 KO mice, in comparison with those expressing an active p53 protein. Our results point out the impact of the p53 signaling pathway in the balance between brain damage and repair, which might condition functional recovery after ICH.Funded by ISCIII (PI18/00265; RD16/0019/0018), FEDER, EU Horizon 2020 Research and Innovation Programme (Grant Agreement 686009), Junta de Castilla y León (CSI151P20; Escalera de Excelencia CLU-2017-03 Cofinanciado por el P.O. FEDER de Castilla y León 14-20); RedHYPOX (SAF2017‐90794‐REDT