title: Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism.
abstract: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC-containing CD34+cells, EPC-mobilizing cytokines - vascular endothelial growth factor and stromal cell-derived factor-1α - and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines neovascularization, brain repair and neurological recovery after ICH. This study is the first in which the Pro allele of Tp53 is linked to vascular repair and ability to functionally recover from stroke.
authors: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Salamanca, Spain.
authors: Cristina
authors: C
authors: Rodríguez
authors: Health Research Institute of Santiago de Compostela, University Clinical Hospital-University of Santiago de Compostela, A Coruña, Spain.
authors: Tomás
authors: T
authors: Sobrino
authors: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Salamanca, Spain.
authors: Jesús
authors: J
authors: Agulla
authors: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Salamanca, Spain.
authors: Verónica
authors: V
authors: Bobo-Jiménez
authors: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Salamanca, Spain.
authors: María E
authors: ME
authors: Ramos-Araque
authors: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.
authors: Juan J
authors: JJ
authors: Duarte
authors: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.
authors: José C
authors: JC
authors: Gómez-Sánchez
authors: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Salamanca, Spain.
authors: Juan P
authors: JP
authors: Bolaños
authors: Health Research Institute of Santiago de Compostela, University Clinical Hospital-University of Santiago de Compostela, A Coruña, Spain.
authors: José
authors: J
authors: Castillo
authors: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca-University of Salamanca, Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Salamanca, Spain.
authors: Ángeles
authors: Á
authors: Almeida
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D054377:Chemokine CXCL12 / Q000097:blood / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism / Q000633:toxicity; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000235:genetics / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D001120:Arginine; D011392:Proline; D017364:Collagenases