Mechanisms for ageing changes in the hepatic sinusoid

我们最近发现，随着年龄的增长，肝脏血管发生了变化，我们称之为假毛细血管化。这些变化包括肝窦内皮细胞增厚，基底膜和胶原沉积，内皮细胞内称为开窗的特殊毛孔显著丢失。这些变化对包括毒素、药物、氧气、激素和脂质在内的许多底物从血液到肝脏的转移产生了深远的影响，从而可能部分解释了老年是许多疾病和药物不良反应的主要风险因素的事实。为了进一步了解这些重要的老化肝脏变化的机制，我们提出了几项研究。首先，将研究卡路里限制对肝血管的影响，因为卡路里限制延缓了主要的衰老过程。其次，我们将研究衰老对F-肌动蛋白、ATP、小窝蛋白-1和血管内皮生长因子的影响，因为这些机制已经确立了调节肝脏血管结构和功能的作用，特别是它们的窗口。最后，我们将确定血管内皮生长因子是否可以逆转肝血管的老化变化，并刺激这些血管内新窗口的形成。我们的研究为老年与疾病易感性之间的必然联系提供了一种机制--基于肝脏的初级衰老变化。除了增加我们对衰老过程中细胞变化的了解，以及参与调节肝内皮细胞及其窗口的基本机制，这项拟议的研究将为开发预防和治疗某些与年龄相关的疾病的治疗干预措施提供基础。

We recently discovered changes in the blood vessels of the liver that occur with old age that we have called pseudocapillarisation. These changes include thickening of the liver sinusoidal endothelium, deposition of basal lamina and collagen, and marked loss of specialized pores within the endothelium called fenestrations. These changes have profound effects on the transfer of many substrates including toxins, drugs, oxygen, hormones and lipids from the blood into the liver and thus may explain in part the fact that old age is the major risk factor for many diseases and adverse drug reactions. To further understand the mechanisms for these important ageing liver changes, we are proposing several studies. First, the effects of caloric restriction on the liver blood vessels will be studied because caloric restriction delays the primary ageing process. Second we will study the effects of ageing on F-actin, ATP, caveolin-1 and VEGF because these mechanisms have established roles in regulating the structure and function of the liver blood vessels and in particular their fenestrations. Finally we will determine whether VEGF can reverse the ageing changes in the liver blood vessels and stimulate the formation of new fenestrations within these blood vessels. Our research provides one mechanism for the inexorable association between old age and susceptibility to disease - based on primary ageing changes in the liver. As well as increasing our understanding of the cellular changes for ageing and the basic mechanisms involved in the regulation of the liver endothelial cells and their fenestrations, this proposed research will provide a foundation for the development of therapeutic interventions for the prevention and treatment of some age-related disorders.