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增厚、基底层和胶原沉积以及内皮内称为开窗的特化孔的显著损失。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转移到肝脏有着深远的影响，因此可以部分解释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衰老肝脏变化的机制，我们提出了几项研究。首先，将研究热量限制对肝脏血管的影响，因为热量限制延缓了原发性衰老过程。其次，我们将研究衰老对F-actin、ATP、caveolin-1和VEGF的影响，因为这些机制在调节肝血管的结构和功能，特别是它们的开窗中起作用。最后，我们将确定VEGF是否可以逆转肝脏血管的老化变化，并刺激这些血管内新开窗的形成。我们的研究提供了一种机制，老年和疾病易感性之间的必然联系-基于肝脏的原发性衰老变化。除了增加我们对衰老的细胞变化以及肝脏内皮细胞及其开窗调节的基本机制的理解外，这项拟议的研究将为预防和治疗一些年龄相关疾病的治疗干预措施的发展提供基础。

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.