| Autor: |
Park HY; Department of Pediatrics, School of Oncology and Reproduction (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands.; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, 6229 ER Maastricht, The Netherlands., van Bruggen VLE; Department of Pediatrics, School of Oncology and Reproduction (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands., Peutz-Kootstra CJ; Department of Pathology, Gelre ziekenhuizen, 7334 DZ Apeldoorn, The Netherlands., Ophelders DRMG; Department of Pediatrics, School of Oncology and Reproduction (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands., Jellema RK; Department of Pediatrics, School of Oncology and Reproduction (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands.; Department of Pediatrics, Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands., Reutelingsperger CPM; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands., Rutten BPF; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, 6229 ER Maastricht, The Netherlands., Wolfs TGAM; Department of Pediatrics, School of Oncology and Reproduction (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands. |
| Abstrakt: |
Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFRβ for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury. |
