Hoenig Michel R, Bianchi Cesario, Sellke Frank W
Clinical Sciences, Royal Brisbane & Women's Hospital, Brisbane, Australia.
Curr Drug Targets. 2008 May;9(5):422-35. doi: 10.2174/138945008784221215.
Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha). This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.
在包括人类在内的成年动物中，骨髓来源的单核细胞可分化为内皮细胞。这些细胞，即内皮祖细胞（EPCs），在多种生理和病理过程的新血管形成中发挥核心作用。EPCs数量具有临床相关性；在血管疾病患者中，EPCs数量可预测严重的临床终点，并且与无明显动脉粥样硬化患者的血管健康状况相关。EPCs表达CXCR4，这使得它们能够归巢到新血管形成的部位。靶组织释放的归巢信号是SDF-1，它是CXCR4的配体。随着SDF-1的释放以及骨髓/外周梯度的逆转，EPCs被动员到外周，在那里它们被招募到表达SDF-1的组织中。SDF-1/CXCR4轴是缺氧、血管生成肽和粒细胞集落刺激因子（G-CSF）动员EPCs的最终共同途径。靶组织中SDF-1的表达、EPCs中CXCR4的表达以及血管生成细胞因子如血管内皮生长因子（VEGF）都受缺氧诱导因子-1α（HIF-1α）调控。本文讨论了相关证据，表明HIF-1α介导的基因编程受抑制是所有心血管危险因素中最根本的，并讨论了用钴或肼屈嗪等现有药物对该系统进行调控。通过稳定HIF-1α蛋白，这些化合物将增强EPCs的动员和功能，从而全面改善心血管健康。本文讨论了为何先前关于EPC移植或用G-CSF动员的研究得出了阴性结果，并提出使用钴和肼屈嗪来增强EPC功能，以克服在血管疾病或心血管危险因素患者中出现的功能失调的EPC表型。
