Mechanisms of hypoxia induced exacerbation of cerebral cavernous malformations

点击翻译按钮获取中文摘要

Cerebral Cavernous Malformations (CCMs) are common neurovascular lesions made of endothelium clusters filled with blood surrounded by gliosis. CCMs affect ~1/200 children and adults, causing a lifetime risk of hemorrhagic strokes and neurologic deficits for which there is no current effective pharmacologic therapy. Loss of function mutations in three CCM genes propels brain vascular changes. However, the propensity of CCM lesions to form in the central nervous system (CNS) parenchyma relative to other tissues has not been fully explained, and the heterogeneity in disease severity suggests that environmental or biological factors (e.g. other genes, neural cells) act as disease modifiers. We and others have demonstrated that increased vascular endothelial growth factor (VEGF) signaling and associated vascular leakage are significant contributors to CCM disease. Our preliminary data show that hypoxic conditions contribute to an aggressive onset and progression of CCM disease. We observed that hypoxia acts as an accelerant of CCM disease by exacerbating the number and size of brain vascular lesions in CCM animal models. We also observed that mouse and human CCM tissue results in increased hypoxia-inducible factor 1 alpha (HIF-1a) activity, and that proliferative astrocytes influence CCM pathogenesis. The proposed study will test the hypothesis that hypoxia exacerbates CCMs through hypoxic programs from astrocytes and endothelium, leading to abnormal vascular development and stroke due to intracranial hemorrhage. Moreover, we hypothesize that intermittent hypoxia (that occurs with patients with obstructive sleep apnea) will further exacerbate CCMs. Specific Aim 1 will test the hypothesis that hypoxia exacerbates CCM formation by elevating hypoxia-driven genes in astrocytes in murine CCM. We will investigate the effect of hypoxia on astrocyte gene expression (e.g., hypoxic program, VEGF) by profiling translated mRNAs obtained from the purification of the EGFP-tagged ribosome in astrocytes in the presence or absence of CCM lesions. Co-culture in vitro models will be used to define the interaction between CCM endothelium and astrocytes that propels vascular dysfunction. Specific Aim 2 will test the hypothesis that hypoxia exacerbates CCM formation by HIF-1a protein stabilization in the brain endothelium in murine CCM. We will investigate the role of endothelial HIF-1a on changes in the endothelial barrier function, gene expression, VEGF signaling using CCM mouse models. Specific Aim 3 will test the hypothesis that intermittent hypoxia exacerbates murine CCM. We will investigate the role of intermittent hypoxia-driven CCM lesion burden, using mouse models of CCM under intermittent hypoxia that partially recapitulates nocturnal oxygen profile in patients with obstructive sleep apnea (OSA). The proposed research may lead to a new therapeutic approach (e.g., combination therapies for activated astrocytes and CCM endothelium) and preventive measures by defining how environmental (e.g., high altitude) or pathological factors (e.g., OSA, chronic lung disease) that alter oxygen levels may act as risk factors for patients affected with CCMs.