Wilson David F, Matschinsky Franz M
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Front Physiol. 2020 Oct 16;11:584891. doi: 10.3389/fphys.2020.584891. eCollection 2020.
Nutrient delivery to the brain presents a unique challenge because the tissue functions as a computer system with in the order of 200,000 neurons/mm. Penetrating arterioles bud from surface arteries of the brain and penetrate downward through the cortex. Capillary networks spread from penetrating arterioles through the surrounding tissue. Each penetrating arteriole forms a vascular unit, with little sharing of flow among vascular units (collateral flow). Unlike cells in other tissues, neurons have to be operationally isolated, interacting with other neurons through specific electrical connections. Neuronal activation typically involves only a few of the cells within a vascular unit, but the local increase in nutrient consumption is substantial. The metabolic response to activation is transmitted to the feeding arteriole through the endothelium of neighboring capillaries and alters calcium permeability of smooth muscle in the wall resulting in modulation of flow through the entire vascular unit. Many age and trauma related brain pathologies can be traced to vascular malfunction. This includes: 1. Physical damage such as in traumatic injury with imposed shear stress as soft tissue moves relative to the skull. Lack of collateral flow among vascular units results in death of the cells in that vascular unit and loss of brain tissue. 2. Age dependent changes lead to progressive increase in vascular resistance and decrease in tissue levels of oxygen and glucose. Chronic hypoxia/hypoglycemia compromises tissue energy metabolism and related regulatory processes. This alters stem cell proliferation and differentiation, undermines vascular integrity, and suppresses critical repair mechanisms such as oligodendrocyte generation and maturation. Reduced structural integrity results in local regions of acute hypoxia and microbleeds, while failure of oligodendrocytes to fully mature leads to poor axonal myelination and defective neuronal function. Understanding and treating age related pathologies, particularly in brain, requires better knowledge of why and how vasculature changes with age. That knowledge will, hopefully, make possible drugs/methods for protecting vascular function, substantially alleviating the negative health and cognitive deficits associated with growing old.
向大脑输送营养物质面临着独特的挑战，因为该组织的功能类似于一个计算机系统，每立方毫米约有200,000个神经元。穿透性小动脉从大脑表面动脉分支出来，并向下穿透皮质。毛细血管网络从穿透性小动脉延伸至周围组织。每个穿透性小动脉形成一个血管单元，血管单元之间几乎没有血流共享（侧支血流）。与其他组织中的细胞不同，神经元必须在功能上相互隔离，通过特定的电连接与其他神经元相互作用。神经元激活通常只涉及一个血管单元内的少数细胞，但局部营养物质消耗的增加却很显著。激活后的代谢反应通过相邻毛细血管的内皮传递至供血小动脉，并改变血管壁平滑肌的钙通透性，从而调节整个血管单元的血流。许多与年龄和创伤相关的脑部疾病都可追溯到血管功能障碍。这包括：1. 物理损伤，如创伤性损伤中软组织相对于颅骨移动时施加的剪切应力。血管单元之间缺乏侧支血流会导致该血管单元中的细胞死亡和脑组织损失。2. 年龄依赖性变化导致血管阻力逐渐增加，组织中的氧气和葡萄糖水平降低。慢性缺氧/低血糖会损害组织能量代谢及相关调节过程。这会改变干细胞的增殖和分化，破坏血管完整性，并抑制关键的修复机制，如少突胶质细胞的生成和成熟。结构完整性降低会导致局部急性缺氧和微出血区域，而少突胶质细胞未能完全成熟会导致轴突髓鞘形成不良和神经元功能缺陷。了解和治疗与年龄相关的疾病，尤其是脑部疾病，需要更好地了解血管为何以及如何随年龄变化。希望这些知识能够催生保护血管功能的药物/方法，从而大幅减轻与衰老相关的负面健康和认知缺陷。
