Venkatesh Pradeep
Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences Sciences (AIIMS), New Delhi, India.
Med Hypothesis Discov Innov Ophthalmol. 2022 Feb 24;10(4):185-190. doi: 10.51329/mehdiophthal1437. eCollection 2021 Winter.
Angiogenesis causes severe vision loss in patients with exudative or wet forms of age-related macular degeneration (AMD). The pathogenesis involves upregulation of several proangiogenic factors, particularly the vascular endothelial growth factor (VEGF). Contrary to the pathogenesis of exudative AMD, molecular events leading to the development of dry AMD remain unclear. Dry AMD is characterized by loss of the retinal pigment epithelium (RPE). The mechanism that triggers RPE cell loss remains unclear. Choriocapillaris development is absent in mice with RPE-specific deletion of VEGF. Moreover, in later life, background VEGF secretion promotes the survival of the RPE and maintains choriocapillaris integrity.
We hypothesized that reduced synthesis of VEGF (hypo-angiogenesis) or abnormalities in its receptors, VEGF receptor-1 (VEGFR1) and VEGFR2, may be involved in the pathogenesis of non-exudative AMD or dry AMD. If the concept of hypo-angiogenesis as a driver for dry AMD is proven, treatment with VEGF or induction of angiogenesis could be considered. Similar attempts at therapeutic angiogenesis have been actively investigated in cardiac and limb ischemia.
The reasons for a patient developing exudative AMD or dry AMD remain poorly understood. Nevertheless, targeting increased VEGF production in patients with exudative AMD using anti-VEGF drugs is highly efficacious in preserving vision. Similarly, dry AMD may be a manifestation of reduced VEGF synthesis (hypo-angiogenesis) and subsequent decreased RPE cell survival. Experimental studies exploring the possibility of reduced VEGF secretion and/or increased receptor resistance/abnormality could pave the way for clinical trials of angiogenesis to treat dry AMD.
血管生成会导致渗出性或湿性年龄相关性黄斑变性（AMD）患者严重视力丧失。其发病机制涉及多种促血管生成因子的上调，尤其是血管内皮生长因子（VEGF）。与渗出性AMD的发病机制相反，导致干性AMD发展的分子事件仍不清楚。干性AMD的特征是视网膜色素上皮（RPE）丧失。触发RPE细胞丧失的机制仍不清楚。VEGF特异性缺失的RPE小鼠缺乏脉络膜毛细血管发育。此外，在晚年，背景VEGF分泌促进RPE的存活并维持脉络膜毛细血管的完整性。
我们推测VEGF合成减少（血管生成不足）或其受体血管内皮生长因子受体-1（VEGFR1）和VEGFR2异常可能参与非渗出性AMD或干性AMD的发病机制。如果血管生成不足作为干性AMD驱动因素的概念得到证实，可以考虑用VEGF治疗或诱导血管生成。在心脏和肢体缺血方面，已经积极研究了类似的治疗性血管生成尝试。
患者发生渗出性AMD或干性AMD的原因仍知之甚少。然而，使用抗VEGF药物靶向渗出性AMD患者中增加的VEGF产生在保护视力方面非常有效。同样，干性AMD可能是VEGF合成减少（血管生成不足）及随后RPE细胞存活率降低的一种表现。探索VEGF分泌减少和/或受体抗性/异常增加可能性的实验研究可能为治疗干性AMD的血管生成临床试验铺平道路。
