Hoffmann J, Feng Y, vom Hagen F, Hillenbrand A, Lin J, Erber R, Vajkoczy P, Gourzoulidou E, Waldmann H, Giannis A, Wolburg H, Shani M, Jaeger V, Weich H A, Preissner K T, Hoffmann S, Deutsch U, Hammes H-P
Medical Clinic and Policlinic 3, Justus-Liebig University Giessen, Giessen, Germany.
FASEB J. 2005 Dec;19(14):2035-6. doi: 10.1096/fj.04-2109fje. Epub 2005 Oct 7.
Pericyte loss and capillary regression are characteristic for incipient diabetic retinopathy. Pericyte recruitment is involved in vessel maturation, and ligand-receptor systems contributing to pericyte recruitment are survival factors for endothelial cells in pericyte-free in vitro systems. We studied pericyte recruitment in relation to the susceptibility toward hyperoxia-induced vascular remodeling using the pericyte reporter X-LacZ mouse and the mouse model of retinopathy of prematurity (ROP). Pericytes were found in close proximity to vessels, both during formation of the superficial and the deep capillary layers. When exposure of mice to the ROP was delayed by 24 h, i.e., after the deep retinal layer had formed [at postnatal (p) day 8], preretinal neovascularizations were substantially diminished at p18. Mice with a delayed ROP exposure had 50% reduced avascular zones. Formation of the deep capillary layers at p8 was associated with a combined up-regulation of angiopoietin-1 and PDGF-B, while VEGF was almost unchanged during the transition from a susceptible to a resistant capillary network. Inhibition of Tie-2 function either by soluble Tie-2 or by a sulindac analog, an inhibitor of Tie-2 phosphorylation, resensitized retinal vessels to neovascularizations due to a reduction of the deep capillary network. Inhibition of Tie-2 function had no effect on pericyte recruitment. Our data indicate that the final maturation of the retinal vasculature and its resistance to regressive signals such as hyperoxia depend on the completion of the multilayer structure, in particular the deep capillary layers, and are independent of the coverage by pericytes.
周细胞丢失和毛细血管消退是早期糖尿病视网膜病变的特征。周细胞募集参与血管成熟，在无周细胞的体外系统中，促成周细胞募集的配体-受体系统是内皮细胞的存活因子。我们使用周细胞报告基因X-LacZ小鼠和早产儿视网膜病变（ROP）小鼠模型，研究了周细胞募集与高氧诱导的血管重塑易感性之间的关系。在浅表和深层毛细血管层形成过程中，均发现周细胞紧邻血管。当将小鼠暴露于ROP的时间推迟24小时，即在视网膜深层形成后（出生后第8天），出生后第18天视网膜前新生血管明显减少。ROP暴露延迟的小鼠无血管区减少了50%。出生后第8天深层毛细血管层的形成与血管生成素-1和血小板衍生生长因子-B的联合上调有关，而在从易感性毛细血管网络向抗性毛细血管网络转变过程中，血管内皮生长因子几乎没有变化。通过可溶性Tie-2或舒林酸类似物（一种Tie-2磷酸化抑制剂）抑制Tie-2功能，由于深层毛细血管网络减少，使视网膜血管对新生血管重新敏感。抑制Tie-2功能对周细胞募集没有影响。我们的数据表明，视网膜血管系统的最终成熟及其对诸如高氧等退行性信号的抗性取决于多层结构的完成，特别是深层毛细血管层的完成，并且与周细胞的覆盖无关。
