Periostin and tenascin-C interaction promotes angiogenesis in ischemic proliferative retinopathy
Periostin and tenascin-C interaction promotes angiogenesis in ischemic proliferative retinopathy
复制标题
DOI：
10.1038/s41598-020-66278-1
复制
发表时间：
2020-06-09
影响因子：
4.6
通讯作者：
Yoshida, Shigeo
中科院分区：
文献类型：
--
作者：
Kubo, Yuki;Ishikawa, Keijiro;Yoshida, Shigeo
缺血性增殖性视网膜病变（IPR），如增殖性糖尿病视网膜病变（PDR）、视网膜静脉阻塞和早产儿视网膜病变是视力丧失的主要原因。我们的前期研究表明骨膜蛋白（PN）和腱生蛋白-C（TNC）参与了IPR的发病机制。然而，PN和TNC在与IPR相关的血管生成中的相互作用仍不清楚。我们发现PDR玻璃体液中PN和TNC浓度之间存在显著相关性。在PDR患者切除的视网膜前纤维血管膜中发现PN和TNC的mRNA和蛋白表达。白细胞介素13（IL-13）可促进人微血管内皮细胞（HRECs）中PN和TNC的mRNA和蛋白表达，免疫共沉淀法显示PN和TNC结合。IL-13促进HREC的血管生成功能。PN或TNC的单一抑制和siRNA的双重抑制了上调的血管生成功能。与野生型小鼠相比，PN敲除、TNC敲除和双敲除小鼠中氧诱导视网膜病变（OIR）小鼠的病理性视网膜前新生血管减弱。无论在体外还是体内，PN抑制对血管生成的抑制作用均强于TNC抑制，且与PN和TNC的双重抑制作用相似。此外，PN敲除小鼠在OIR视网膜的视网膜前新生血管中表现出很少的TNC表达。我们的研究结果表明，PN和TNC的相互作用促进视网膜前血管生成，PN是一个有效的治疗靶点，如PDR的IPR。
Ischemic proliferative retinopathy (IPR), such as proliferative diabetic retinopathy (PDR), retinal vein occlusion and retinopathy of prematurity is a major cause of vision loss. Our previous studies demonstrated that periostin (PN) and tenascin-C (TNC) are involved in the pathogenesis of IPR. However, the interactive role of PN and TNC in angiogenesis associated with IPR remain unknown. We found significant correlation between concentrations of PN and TNC in PDR vitreous humor. mRNA and protein expression of PN and TNC were found in pre-retinal fibrovascular membranes excised from PDR patients. Interleukin-13 (IL-13) promoted mRNA and protein expression of PN and TNC, and co-immunoprecipitation assay revealed binding between PN and TNC in human microvascular endothelial cells (HRECs). IL-13 promoted angiogenic functions of HRECs. Single inhibition of PN or TNC and their dual inhibition by siRNA suppressed the up-regulated angiogenic functions. Pathological pre-retinal neovessels of oxygen-induced retinopathy (OIR) mice were attenuated in PN knock-out, TNC knock-out and dual knock-out mice compared to wild-type mice. Both in vitro and in vivo, PN inhibition had a stronger inhibitory effect on angiogenesis compared to TNC inhibition, and had a similar effect to dual inhibition of PN and TNC. Furthermore, PN knock-out mice showed scant TNC expression in pre-retinal neovessels of OIR retinas. Our findings suggest that interaction of PN and TNC facilitates pre-retinal angiogenesis, and PN is an effective therapeutic target for IPR such as PDR.