Hypoxia/Reoxygenation & Regulatory Mechanisms

缺氧/复氧

• 批准号: 6895945
• 负责人: RALPH G DACEY
• 金额: $ 35.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895945
• 关键词: arterioles; astrocytes; biological signal transduction; brain circulation; calcium channel blockers; calcium flux; cerebral artery; cerebral ischemia /hypoxia; laboratory rat; nitric oxide synthase; reperfusion; tissue /cell culture; vascular endothelium; vascular smooth muscle; vasoconstriction; vasodilation; vasodilators; video microscopy

DESCRIPTION (provided by applicant): This project tests the hypotheses that parenchymal astrocytes (ACs) contribute to the constriction of cerebral penetrating arterioles (PAs) after hypoxia and reoxygenation (H/RO), and that H/RO-induced arteriolar constriction can be ameliorated by transducing nitric oxide synthase (NOS). Ischemia/Reperfusion constricts intracortical cerebral arterioles in vivo which may contribute to post-ischemic oligemia. H/RO causes vasoconstriction in isolated cortical PAs. It is not known how parenchymal Acs exacerbate vasoconstriction in PAs after HtRO. Since PAs are the last regulator of blood flow to the cortical tissue, even a small additional vasoconstriction would greatly increase vascular resistance and thereby contribute to postischemic oligemia observed in vivo. An H/RO-induced impairment in NO production by PAs may also contribute to the net vasoconstriction. Reducing this vasoconstrictor response by NOS transduction may be instrumental in salvaging cerebral neuronal tissue after stroke. Experiments will be performed in vitro. Rat PAs will be isolated, cannulated, and observed by video microscopy. The vessels will be subjected to hypoxia for one hour. (1) We will test if astrocyte contact exacerbates penetrating arteriolar vasoconstriction after H/RO. We will determine if postischemic glucose deprivation exacerbates H/RO-induced constriction. (2) We will determine if and which reactive oxygen species (ROS: O2", H202, peroxynitrite) is released from ACs to causes the enhanced arteriolar-constriction. ACs exposed to H/RO may release ROS which deactivate NO, but also other vasoconstrictors. The use of specific inhibitors will reveal the participation of the various mediators in H/RO-induced vasoconstriction. (3) We will test if transduction of NOS into PAs ameliorates H/RO-induced constriction. Impairment of endothelial NOS after cerebral ischemia is a possible cause for the observed vessel constriction. We will transduce inducible NOS (iNOS) protein directly into PAs in vitro and in cultured cerebral microvascular cells. The iNOS protein was recently found to be a beneficial tool to treat endothelial dysfunction. Our studies will give us crucial information on possible treatments targeted precisely to prevent post-ischemic intracerebral arteriolar constriction and to improve post-ischemic microvascular perfusion in vivo.

描述（由申请人提供）：该项目测试了实质星形胶质细胞（ACS）的假设有助于在缺氧和再氧（H/RO）（H/RO）之后的大脑穿透性小动脉（PAS）的限制，并且H/RO诱导的小动脉约束可以通过透射NIT氧化氧化物（Nitric Nitric Synthasese（Nitric Synthases）（nit nit Syntthase）减轻。缺血/再灌注会在体内收缩心脏内脑小动脉，这可能导致缺血后的寡血症。 H/RO在分离的皮质PA中引起血管收缩。尚不清楚htro后PAS中的实质ACS加剧血管收缩。由于PAS是流向皮质组织的最后一次调节剂，因此即使是少量的其他血管收缩也会大大增加血管耐药性，从而有助于体内观察到的缺血后寡血症。 H/RO诱导的NO生产损伤也可能导致血管收缩净。通过NOS转导减少这种血管收缩反应可能在中风后挽救脑神经元组织中发挥作用。实验将在体外进行。大鼠PA将通过视频显微镜分离，插管和观察。该血管将遭受缺氧一小时的缺氧。 （1）我们将测试星形胶质细胞接触是否加剧了H/RO后穿透小动脉血管收缩。我们将确定缺血后葡萄糖剥夺是否加剧了H/RO诱导的收缩。 （2）我们将确定是否和哪些活性氧（ROS：O2”，H202，过氧亚硝酸盐）从ACS释放出来，从而导致动脉收缩增强。暴露于H/RO的AC可能会释放ROS，而ROS可能会失效，但其他血压抑制器的使用将显示出其他差异的参与者。将在脑部缺血后，将NOS的转化改善H/RO诱导的内皮损伤。功能障碍。我们的研究将为我们提供有关可能治疗的重要信息，以防止缺血后小动脉收缩并改善体内缺血后的微血管灌注。