Liu Miaomiao, Zhao Peiquan, Feng Huazhang, Yang Yuan, Zhang Xuerui, Chen Enguang, Xiao Haodong, Luo Jia, Chen Han, Yin Jiawei, Lin Min, Mao Ruixue, Zhu Xingping, Li Jing, Fei Ping
Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Naval Healthcare Information Center, PLA Naval Medical University, Shanghai, China.
FASEB J. 2025 Jan 15;39(1):e70262. doi: 10.1096/fj.202401903R.
Retinal pathological angiogenesis (PA) is a common hallmark in proliferative retinopathies, including age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and retinopathy of prematurity (ROP). The mechanisms underlying PA is complex and incompletely understood. In this study, we investigated the role of extracellular matrix (ECM) protein biglycan (BGN) in PA using an oxygen-induced retinopathy (OIR) mouse model, along with hypoxia (1% O) conditions for incubating pericytes and endothelial cells in vitro. We found a significant upregulation of Bgn in the retinas of OIR mice. Intravitreal injection of Bgn-specific small interfering RNA (siRNA) in OIR mice at postnatal day 12 (P12) effectively curbed retinal PA at P17. Using cultured cells, we found that BGN expression in pericytes was highly sensitive to hypoxic stimulation compared to endothelial cells. We further showed that BGN stimulated retinal PA via the upregulation of C-X-C motif chemokine ligand 12 (CXCL12). Inhibition of the CXCL12-CXCR4 axis effectively diminished PA in OIR mouse. In conclusion, our study demonstrated the stimulatory role of BGN in retinal PA, identified the link between BGN and CXCL12 expression, and further highlighted the role of pericytes in retinal PA.
视网膜病理性血管生成（PA）是增殖性视网膜病变的一个常见特征，包括年龄相关性黄斑变性（AMD）、增殖性糖尿病视网膜病变（PDR）和早产儿视网膜病变（ROP）。PA的潜在机制复杂且尚未完全了解。在本研究中，我们使用氧诱导视网膜病变（OIR）小鼠模型，以及在体外培养周细胞和内皮细胞的低氧（1% O₂）条件，研究了细胞外基质（ECM）蛋白双糖链蛋白聚糖（BGN）在PA中的作用。我们发现OIR小鼠视网膜中Bgn显著上调。在出生后第12天（P12）向OIR小鼠玻璃体内注射Bgn特异性小干扰RNA（siRNA），在P17时有效抑制了视网膜PA。使用培养细胞，我们发现与内皮细胞相比，周细胞中BGN的表达对低氧刺激高度敏感。我们进一步表明，BGN通过上调C-X-C基序趋化因子配体12（CXCL12）刺激视网膜PA。抑制CXCL12-CXCR4轴可有效减少OIR小鼠的PA。总之，我们的研究证明了BGN在视网膜PA中的刺激作用，确定了BGN与CXCL12表达之间的联系，并进一步突出了周细胞在视网膜PA中的作用。
