The mechanisms and role of postnatal cerebral vascular remodeling

描述（由申请人提供）：脑血流量受到严格调节，以满足大脑的大量能量需求。然而，在发育过程中如何实现血管化程度和区域代谢需求之间的精确匹配仍不清楚。由于大量的突触形成，大脑的能量需求在出生后的早期急剧增加。然而，出生后血管重塑的过程，这可能是建立一个适当的血管网络的关键，仍然知之甚少。这一建议旨在增加我们对出生后血管重构的理解。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，而这一过程的短暂中断会对神经元连接产生永久性影响。为了验证这一点，我们将使用各种遗传和药理学方法来改变固定组织和活体小鼠大脑中的神经元活动以及血管和神经元成像。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动来确定神经元活动对血管重塑的影响。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通性的影响。此外，我们测试了血管重塑是否发生在类似于出生后神经元连接完善所观察到的关键时期。总之，这些研究将极大地促进我们对出生后血管重塑机制的理解，这可能对满足大脑代谢需求和维持神经元健康至关重要。

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.