Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity
Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity
复制标题
DOI：
10.1172/jci200317808
复制
发表时间：
2003-07-01
影响因子：
15.9
通讯作者：
Smith, LEH
中科院分区：
文献类型：
--
作者：
Shih, SC;Ju, MH;Smith, LEH
给未成熟新生儿供氧抑制视网膜中VEGF-A的表达，导致灾难性的血管损失，引发早产儿视网膜病变。为了研究负责发育中视网膜血管存活的机制，我们表征了两种VEGF-A受体，VEGF受体-1（VEGFR-1，也称为Flt-1）和VEGF受体-2（VEGFR-2，也称为Flk-1）。令人惊讶的是，这两种VEGF-A受体在小鼠正常视网膜发育期间明显不同。在产后5天（PS），VEGFR-1蛋白与视网膜血管共定位，而VEGFR-2仅在神经视网膜中检测到。实时定量RT-PCR结果显示，从P3（早期血管化）到P26（完全血管化），视网膜中VEGFR-1 mRNA的表达增加了60倍，而VEGFR-2 mRNA的表达无显著变化。胎盘生长因子-1（PlGF-1），专门结合VEGFR-1，减少高氧诱导的视网膜血管闭塞从22.2%到S。1%，而VEGF-E，其专门结合VEGFR-2，对血管存活没有影响。重要的是，在相同条件下，PlGF-1在（a）正常血管生长、（B）高氧诱导的缺血后的再血管化或（c）血管增殖阶段期间不增加血管增殖，表明支持血管存活的选择性功能。我们的结论是，VEGFR-1是维持新生儿视网膜的血管系统的关键，并通过PIGF-1的VEGFR-1的激活是一种选择性的策略，用于防止氧诱导的视网膜缺血，而不会引起视网膜新生血管。
Oxygen administration to immature neonates suppresses VEGF-A expression in the retina, resulting in the catastrophic vessel loss that initiates retinopathy of prematurity. To investigate the mechanisms responsible for survival of blood vessels in the developing retina, we characterized two VEGF-A receptors, VEGF receptor-1 (VEGFR-1, also known as Flt-1) and VEGF receptor-2 (VEGFR-2, also known as Flk-1). Surprisingly, these two VEGF-A receptors differed markedly during normal retinal development in mice. At 5 days postpartum (PS), VEGFR-1 protein was colocalized with retinal vessels, whereas VEGFR-2 was detected only in the neural retina. Real-time RT-PCR identified a 60-fold induction of VEGFR-1 mRNA in retina from P3 (early vascularization) to P26 (fully vascularized), and no significant change in VEGFR-2 mRNA expression. Placental growth factor-1 (PlGF-1), which exclusively binds VEGFR-1, decreased hyperoxia-induced retinal vaso-obliteration from 22.2% to S. 1%, whereas VEGF-E, which exclusively binds VEGFR-2, had no effect on blood vessel survival. Importantly, under the same conditions, PlGF-1 did not increase vasoproliferation during (a) normal vessel growth, (b) revascularization following hyperoxia-induced ischemia, or (c) the vasoproliferative phase, indicating a selective function supporting blood vessel survival. We conclude that VEGFR-1 is critical in maintaining the vasculature of the neonatal retina, and that activation of VEGFR-1 by PlGF-1 is a selective strategy for preventing oxygen-induced retinal ischemia without provoking retinal neovascularization.