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.
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DOI：
10.1172/jci17808
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发表时间：
2003-07
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影响因子：
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通讯作者：
S. Shih;M. Ju;Nan Liu;Lois E. H. Smith
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作者：
S. Shih;M. Ju;Nan Liu;Lois E. H. Smith
未成熟新生儿吸氧会抑制视网膜中 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。为了研究发育中视网膜中血管存活的机制，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过程中存在显着差异。产后 5 天 (P5)，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 RT-PCR 发现，从 P3（早期血管化）到 P26（完全血管化），视网膜中 VEGFR-1 mRNA 诱导了 60 倍，而 VEGFR-2 mRNA 表达没有显着变化。胎盘生长因子-1 (PlGF-1) 专门结合 VEGFR-1，可将高氧诱导的视网膜血管闭塞从 22.2% 降低至 5.1%，而 VEGF-E 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) 期间没有增加血管增殖。正常血管生长，(b)。高氧诱导的缺血后血运重建，或（c）。血管增殖期，表明支持血管存活的选择性功能。我们得出的结论是，VEGFR-1 对于维持新生儿视网膜的脉管系统至关重要，并且 PlGF-1 激活 VEGFR-1 是预防氧诱导的视网膜缺血而不引起视网膜新生血管形成的选择性策略。
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 (P5), 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 5.1%, 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.