Lofqvist Chatarina, Chen Jing, Connor Kip M, Smith Alexandra C H, Aderman Christopher M, Liu Nan, Pintar John E, Ludwig Thomas, Hellstrom Ann, Smith Lois E H
Department of Ophthalmology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10589-94. doi: 10.1073/pnas.0702031104. Epub 2007 Jun 13.
Vessel loss precipitates many diseases. In particular, vessel loss resulting in hypoxia induces retinal neovascularization in diabetic retinopathy and in retinopathy of prematurity (ROP), major causes of blindness. Here we define insulin-like growth factor binding protein-3 (IGFBP3) as a new modulator of vascular survival and regrowth in oxygen-induced retinopathy. In IGFBP3-deficient mice, there was a dose-dependent increase in oxygen-induced retinal vessel loss. Subsequent to oxygen-induced retinal vessel loss, Igfbp3(-/-) mice had a 31% decrease in retinal vessel regrowth versus controls after returning to room air. No difference in serum insulin-like growth factor 1 (IGF1) levels was observed among groups. Wild-type mice treated with exogenous IGFBP3 had a significant increase in vessel regrowth. This correlated with a 30% increase in endothelial progenitor cells in the retina at postnatal day 15, indicating that IGFBP3 could be serving as a progenitor cell chemoattractant. In a prospective clinical study, we measured IGFBP3 (and IGF1) plasma levels weekly and examined retinas in all premature infants born at gestational ages <32 weeks at high risk for ROP. The mean level of IGFBP3 at 30-35 weeks postmenstrual age (PMA) for infants with proliferative ROP (ROP stages 3>, n = 13) was 802 microg/liter, and for infants with no ROP (ROP stage 0, n = 38) the mean level was 974 microg/liter (P < 0.03). These results suggest that IGFBP3, acting independently of IGF1, helps to prevent oxygen-induced vessel loss and to promote vascular regrowth after vascular destruction in vivo in a dose-dependent manner, resulting in less retinal neovascularization.
血管缺失会引发多种疾病。特别是，导致缺氧的血管缺失会在糖尿病性视网膜病变和早产儿视网膜病变（ROP）中诱发视网膜新生血管形成，而这两种病变是失明的主要原因。在此，我们将胰岛素样生长因子结合蛋白3（IGFBP3）定义为氧诱导性视网膜病变中血管存活和再生的一种新调节因子。在IGFBP3基因缺陷小鼠中，氧诱导的视网膜血管缺失呈剂量依赖性增加。在氧诱导的视网膜血管缺失后，与对照组相比，Igfbp3（-/-）小鼠在恢复至室内空气环境后视网膜血管再生减少了31%。各实验组之间未观察到血清胰岛素样生长因子1（IGF1）水平存在差异。用外源性IGFBP3处理的野生型小鼠血管再生显著增加。这与出生后第15天视网膜中内皮祖细胞增加30%相关，表明IGFBP3可能作为祖细胞趋化因子发挥作用。在一项前瞻性临床研究中，我们每周测量所有孕周<32周、患ROP高危的早产儿的血浆IGFBP3（和IGF1）水平，并检查其视网膜。患有增殖性ROP（ROP分期>3期，n = 13）的婴儿在月经龄（PMA）30 - 35周时的IGFBP3平均水平为802微克/升，而未患ROP（ROP分期0期，n = 38）的婴儿的平均水平为974微克/升（P < 0.03）。这些结果表明，IGFBP3独立于IGF1发挥作用，有助于预防氧诱导的血管缺失，并以剂量依赖性方式促进体内血管破坏后的血管再生，从而减少视网膜新生血管形成。
