The mechanisms and role of postnatal cerebral vascular remodeling

产后脑血管重塑的机制和作用

• 批准号: 8013063
• 负责人: Christina B Whiteus
• 金额: $ 3.38万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013063
• 关键词: Action Potentials; Age; Angiogenesis Inhibition; Area; Asses; Astrocytes; Blood Vessels; Botulinum Toxins; Brain; Cell Proliferation; Cell physiology; Cells; Cerebrovascular Circulation; Cerebrum; Chloride Channels; Confocal Microscopy; Development; Embryonic Development; Endothelial Cells; Epilepsy; Exercise; Future; Genetic; Glucose; Goals; Green Fluorescent Proteins; Health; Image; Injection of therapeutic agent; Life; Long-Term Effects; Measures; Metabolic; Methods; Microscopy; Modeling; Monitor; Motor Cortex; Mus; Nature; Neonatal; Neurons; Organ; Oxygen; Pattern; Pharmacological Treatment; Process; Proteins; Role; Slice; Staging; Stereotyping; Structure; Synapses; System; Techniques; Testing; Tetanus Toxin; Time; Transgenic Mice; Vascular Endothelial Growth Factors; Vascular remodeling; Vascularization; Vertebral column; angiogenesis; cell type; critical period; density; in vivo; inhibitor/antagonist; meetings; neonate; neuron loss; postnatal; research study; response; synaptogenesis; tissue fixing; treatment effect; two-photon

DESCRIPTION (provided by applicant): Cerebral blood flow is tightly regulated to meet the brain's large energetic needs. Yet it remains unclear how a precise matching between the degree of vascularization and regional metabolic demands is achieved during development. The brain's energetic needs increase dramatically in the early postnatal period due to massive synaptogenesis. However, the process of postnatal vascular remodeling, which could be critical for establishing an adequate vascular network, remains poorly understood. This proposal aims at increasing our understanding of postnatal vascular remodeling. We hypothesize that neuronal activity promotes postnatal vascular remodeling via vascular endothelial growth factor (VEGF) and that transient disruption of this process has permanent consequences on neuronal connectivity. To test this, we will use a variety of genetic and pharmacological methods to alter neuronal activity as well as vascular and neuronal imaging in fixed tissues and the living mouse brain using two-photon microscopy. In specific aim 1, we characterize the patterns of vascular remodeling by measuring the degree of angiogenesis, sprouting and pruning and correlate it with regional synaptic density. In aim 2, we determine the effects of neuronal activity on vascular remodeling by altering neuronal activity using pharmacological and genetic methods. We also measure the effect of neuronal activity on levels of VEGF. In aim 3, we determine the effects of altering postnatal vascular remodeling on neuronal structure and connectivity. Additionally, we test whether vascular remodeling occurs within a critical period analogous to that observed with postnatal refinement of neuronal connections. Together, these studies will greatly advance our understanding of the mechanisms of postnatal vascular remodeling which may be critically important in meeting the metabolic demands of the brain and maintaining the health of neurons.

描述（由申请人提供）：脑血流受到严格调节，以满足大脑的大量能量需求。然而，目前仍不清楚如何精确匹配血管化程度和区域代谢需求是在发展过程中实现的。由于大量的突触发生，大脑的能量需求在出生后早期急剧增加。然而，出生后血管重塑的过程，这可能是建立一个足够的血管网络的关键，仍然知之甚少。该建议旨在增加我们对出生后血管重塑的理解。我们假设神经元活动通过血管内皮生长因子（VEGF）促进出生后血管重塑，并且该过程的短暂中断对神经元连接具有永久性后果。为了测试这一点，我们将使用各种遗传和药理学方法来改变神经元的活动，以及血管和神经元成像在固定的组织和活的小鼠大脑使用双光子显微镜。在具体目标1中，我们通过测量血管生成、发芽和修剪的程度来表征血管重塑的模式，并将其与区域突触密度相关联。在目标2中，我们通过使用药理学和遗传学方法改变神经元活性来确定神经元活性对血管重塑的影响。我们还测量了神经元活动对VEGF水平的影响。在目标3中，我们确定改变出生后血管重塑对神经元结构和连接的影响。此外，我们测试血管重塑是否发生在一个关键时期类似于观察到的产后细化的神经元连接。总之，这些研究将极大地推进我们对出生后血管重塑机制的理解，这对于满足大脑的代谢需求和维持神经元的健康至关重要。