RESUMO
Endothelial dysfunction and blood-brain barrier (BBB) leakage have been suggested as a fundamental role in the development of cerebral small vessel disease (SVD) pathology. However, the molecular and cellular mechanisms that link cerebral hypoxic hypoperfusion and BBB disruption remain elusive. Sphingosine-1-phosphate (S1P) regulates the BBB integrity by binding to its receptor isoform 1 (S1PR1) on endothelial cells. This study tested the hypothesis that hypoxic hypoperfusion triggers capillary endothelial S1PR1 disruption, which compromises BBB integrity and leads to SVD-related neuropathological changes, using a chronic hypoxic hypoperfusion model with BBB dysfunction. Spontaneously hypertensive rat stroke-prone underwent unilateral carotid artery occlusion (UCAO) followed by a Japanese permissive diet (JPD) for up to 9 weeks. Selective S1PR1 agonist SEW2871 was used to activate S1PR1. Significant progressive reduction of S1PR1 was detected in rat brains from 4 to 9 weeks following UCAO/JPD onset, which was also detected in cerebral vasculature in human SVD. S1PR1 activation by SEW2871 significantly reduced lesions in both white and grey matter and ameliorated cerebral blood flow. SEW2871 reversed the loss of endothelial S1PR1 and tight junction proteins, and significantly attenuated UCAO/JPD induced accumulation of neuronal phosphorylated tau. This protective role of SEW2871 is associated with promotion of Akt phosphorylation and inhibition of S1PR2/Erk1/2 activation. Our data suggest S1PR1 signalling as a potential molecular mechanistic basis that links hypoxic hypoperfusion with BBB damage in the neuropathological cascades in SVD. The reversal of BBB disruption through pharmacological intervention of S1PR1 signalling likely reveals a novel therapeutic target for SVD.
RESUMO
PURPOSE: To explore the experiences and needs of African American (AA) children and adolescents who were identified by a cancer survivor in their family as providing substantial supportive care during diagnosis and treatment. PARTICIPANTS & SETTING: 5 AA young adults who provided care and support to a family member with cancer when they were aged 7-19 years and 4 cancer survivors from a northeastern U.S. city. METHODOLOGIC APPROACH: Focus groups and interviews were conducted, recorded, transcribed, and analyzed using content analysis until thematic saturation was reached. FINDINGS: Themes focused on AA young supporters' lack of cancer-related information, reduced ability to communicate needs, and challenged views of themselves, relationships, faith, and the future at the time that they provided support. IMPLICATIONS FOR NURSING: Nurses can support AA children and adolescents in caregiving roles by assessing their needs and providing information on diagnosis and treatment. In addition, nurses can conduct research on culturally adapted interventions that can better support AA children and adolescents caring for a parent or grandparent with cancer.
