Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Curr Vasc Pharmacol. 2013 Sep;11(5):544-63. doi: 10.2174/1570161111311050002.
Hypoxia can induce functional and structural vascular remodeling by changing the expression of trophic factors to promote homeostasis. While most experimental approaches have been focused on functional remodeling, structural remodeling can reflect changes in the abundance and organization of vascular proteins that determine functional remodeling. Better understanding of age-dependent hypoxic macrovascular remodeling processes of the cerebral vasculature and its clinical implications require knowledge of the vasotrophic factors that influence arterial structure and function. Hypoxia can affect the expression of transcription factors, classical receptor tyrosine kinase factors, non-classical G-protein coupled factors, catecholamines, and purines. Hypoxia's remodeling effects can be mediated by Hypoxia Inducible Factor (HIF) upregulation in most vascular beds, but alterations in the expression of growth factors can also be independent of HIF. PPARγ is another transcription factor involved in hypoxic remodeling. Expression of classical receptor tyrosine kinase ligands, including vascular endothelial growth factor, platelet derived growth factor, fibroblast growth factor and angiopoietins, can be altered by hypoxia which can act simultaneously to affect remodeling. Tyrosine kinase-independent factors, such as transforming growth factor, nitric oxide, endothelin, angiotensin II, catecholamines, and purines also participate in the remodeling process. This adaptation to hypoxic stress can fundamentally change with age, resulting in different responses between fetuses and adults. Overall, these mechanisms integrate to assure that blood flow and metabolic demand are closely matched in all vascular beds and emphasize the view that the vascular wall is a highly dynamic and heterogeneous tissue with multiple cell types undergoing regular phenotypic transformation.
缺氧可以通过改变营养因子的表达来诱导功能和结构的血管重塑，从而促进内稳态。虽然大多数实验方法都集中在功能重塑上，但结构重塑可以反映血管蛋白丰度和组织的变化，而这些变化决定了功能重塑。要更好地理解与年龄相关的脑血管大血管重塑过程及其临床意义，就需要了解影响动脉结构和功能的血管营养因子。缺氧可以影响转录因子、经典受体酪氨酸激酶因子、非经典 G 蛋白偶联因子、儿茶酚胺和嘌呤的表达。在大多数血管床中，缺氧诱导因子（HIF）的上调可以介导缺氧的重塑作用，但生长因子表达的改变也可以独立于 HIF。过氧化物酶体增殖物激活受体γ（PPARγ）是另一个参与缺氧重塑的转录因子。经典受体酪氨酸激酶配体的表达，包括血管内皮生长因子、血小板衍生生长因子、成纤维细胞生长因子和血管生成素，都可以被缺氧改变，这些改变可以同时作用于重塑。酪氨酸激酶非依赖性因子，如转化生长因子、一氧化氮、内皮素、血管紧张素 II、儿茶酚胺和嘌呤，也参与了重塑过程。这种对缺氧应激的适应会随着年龄的增长而发生根本变化，导致胎儿和成人之间的反应不同。总的来说，这些机制整合起来可以确保所有血管床的血流和代谢需求都得到密切匹配，并强调了血管壁是一个具有多种细胞类型、经常发生表型转化的高度动态和异质组织的观点。
