Diabetes Biology Lab, Division of Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud P.O, Thiruvananthapuram, 695514, Kerala, India.
Diabetes Biology Lab, Division of Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud P.O, Thiruvananthapuram, 695514, Kerala, India.
Pharmacol Res. 2020 Aug;158:104858. doi: 10.1016/j.phrs.2020.104858. Epub 2020 May 11.
Angiogenesis is a finely co-ordinated, multi-step developmental process of the new vascular structure. Even though angiogenesis is regularly occurring in physiological events such as embryogenesis, in adults, it is restricted to specific tissue sites where rapid cell-turnover and membrane synthesis occurs. Both excessive and insufficient angiogenesis lead to vascular disorders such as cancer, ocular diseases, diabetic retinopathy, atherosclerosis, intra-uterine growth restriction, ischemic heart disease, stroke etc. Occurrence of altered lipid profile and vascular lipid deposition along with vascular disorders is a hallmark of impaired angiogenesis. Among lipoproteins, lipoprotein(a) needs special attention due to the presence of a multi-kringle protein subunit, apolipoprotein(a) [apo(a)], which is structurally homologous to many naturally occurring anti-angiogenic proteins such as plasminogen and angiostatin. Researchers have constructed different recombinant forms of apo(a) (rhLK68, rhLK8, RHACK2, KV-11, and AU-6) and successfully exploited its potential to inhibit unwanted angiogenesis during tumor metastasis and retinal neovascularization. Similar to naturally occurring anti-angiogenic proteins, apo(a) can directly interfere with angiogenic signaling pathways. Besides this, apo(a) can also exert its anti-angiogenic effect indirectly by inducing endothelial cell apoptosis, by inhibiting endothelial progenitor cell functions or by upregulating nuclear factors in endothelial cells via apo(a)-bound oxPLs. However, the impact of the anti-angiogenic potential of native apo(a) during physiological angiogenesis in embryos and wounded tissues is not yet explored. In this context, we review the studies so far done to demonstrate the anti-angiogenic activity of apo(a) and the recent developments in using apo(a) as a therapeutic agent to treat impaired angiogenesis during vascular disorders, with emphasis on the gaps in the literature.
血管生成是新血管结构的精细协调的多步骤发育过程。尽管血管生成在胚胎发生等生理事件中经常发生，但在成年人中，它仅限于快速细胞更新和膜合成发生的特定组织部位。过度和不足的血管生成都会导致血管紊乱，如癌症、眼部疾病、糖尿病性视网膜病变、动脉粥样硬化、宫内生长受限、缺血性心脏病、中风等。改变的脂质谱和血管脂质沉积以及血管紊乱的发生是血管生成受损的标志。在脂蛋白中，由于存在多kringle 蛋白亚基载脂蛋白(a) [apo(a)]，脂蛋白(a)需要特别关注，apo(a)在结构上与许多天然存在的抗血管生成蛋白（如纤溶酶原和血管抑素）同源。研究人员构建了不同的 apo(a)重组形式（rhLK68、rhLK8、RHACK2、KV-11 和 AU-6），并成功利用其潜力抑制肿瘤转移和视网膜新生血管形成过程中不必要的血管生成。与天然存在的抗血管生成蛋白类似，apo(a)可以直接干扰血管生成信号通路。除此之外，apo(a)还可以通过诱导内皮细胞凋亡、抑制内皮祖细胞功能或通过 apo(a)结合的 oxPL 上调内皮细胞中的核因子，间接发挥其抗血管生成作用。然而，天然 apo(a)在胚胎和受伤组织中的生理性血管生成中的抗血管生成潜力尚未得到探索。在这种情况下，我们综述了迄今为止的研究，以证明 apo(a)的抗血管生成活性以及最近利用 apo(a)作为治疗剂治疗血管紊乱期间受损的血管生成的进展，重点介绍文献中的空白。
