Adair Thomas H
Dept. of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216-4505, USA.
Am J Physiol Regul Integr Comp Physiol. 2005 Aug;289(2):R283-R296. doi: 10.1152/ajpregu.00840.2004.
The importance of metabolic factors in the regulation of angiogenesis is well understood. An increase in metabolic activity leads to a decrease in tissue oxygenation causing tissues to become hypoxic. The hypoxia initiates a variety of signals that stimulate angiogenesis, and the increase in vascularity that follows promotes oxygen delivery to the tissues. When the tissues receive adequate amounts of oxygen, the intermediate effectors return to normal levels, and angiogenesis ceases. An emerging concept is that adenosine released from hypoxic tissues has an important role in driving the angiogenesis. The following feedback control hypothesis is proposed: AMP is dephosphorylated by ecto-5'-nucleotidase, producing adenosine under hypoxic conditions in the extracellular space adjacent to a parenchymal cell (e.g., cardiomyocyte, skeletal muscle fiber, hepatocyte, etc.). Extracellular adenosine activates A(2) receptors, which stimulates the release of vascular endothelial growth factor (VEGF) from the parenchymal cell. VEGF binds to its receptor (VEGF receptor 2) on endothelial cells, stimulating their proliferation and migration. Adenosine can also stimulate endothelial cell proliferation independently of VEGF, which probably involves modulation of other proangiogenic and antiangiogenic growth factors and perhaps an intracellular mechanism. In addition, hemodynamic factors associated with adenosine-induced vasodilation may have a role in the development and remodeling of the vasculature. Once a new capillary network has been established, and the diffusion/perfusion capabilities of the vasculature are sufficient to supply the parenchymal cells with adequate amounts of oxygen, adenosine and VEGF as well as other proangiogenic and antiangiogenic growth factors return to near-normal levels, thus closing the negative feedback loop. The available data indicate that adenosine might be an essential mediator for up to 50-70% of the hypoxia-induced angiogenesis in some situations; however, additional studies in intact animals will be required to fully understand the quantitative importance of adenosine.
代谢因子在血管生成调节中的重要性已得到充分理解。代谢活动的增加会导致组织氧合作用降低，使组织变得缺氧。缺氧会引发多种刺激血管生成的信号，随后血管增多促进了氧气向组织的输送。当组织获得足够的氧气时，中间效应物会恢复到正常水平，血管生成也会停止。一个新出现的概念是，缺氧组织释放的腺苷在驱动血管生成中起重要作用。现提出以下反馈控制假说：在与实质细胞（如心肌细胞、骨骼肌纤维、肝细胞等）相邻的细胞外空间中，缺氧条件下胞外5'-核苷酸酶将AMP去磷酸化，产生腺苷。细胞外腺苷激活A(2)受体，刺激实质细胞释放血管内皮生长因子（VEGF）。VEGF与其在内皮细胞上的受体（VEGF受体2）结合，刺激内皮细胞的增殖和迁移。腺苷还可独立于VEGF刺激内皮细胞增殖，这可能涉及对其他促血管生成和抗血管生成生长因子的调节，或许还涉及一种细胞内机制。此外，与腺苷诱导的血管舒张相关的血流动力学因素可能在血管系统的发育和重塑中起作用。一旦建立了新的毛细血管网络，且血管系统的扩散/灌注能力足以向实质细胞提供足够的氧气，腺苷、VEGF以及其他促血管生成和抗血管生成生长因子就会恢复到接近正常的水平，从而关闭负反馈回路。现有数据表明，在某些情况下，腺苷可能是高达50 - 70%的缺氧诱导血管生成的关键介质；然而，需要在完整动物中进行更多研究，以充分了解腺苷的定量重要性。
