The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels
The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels
复制标题
DOI：
10.1016/j.ajpath.2016.11.007
复制
发表时间：
2017-03-01
影响因子：
6
通讯作者：
Lorenzi, Mara
中科院分区：
文献类型：
--
作者：
Dagher, Zeina;Gerhardinger, Chiara;Lorenzi, Mara
转化生长因子-β在细胞外基质产生和血管重塑中的作用，以及转化生长因子-β在糖尿病中表达和信号的增加，提示转化生长因子-β在糖尿病视网膜病变和肾病的微血管病变中起重要作用。为了研究增加的转化生长因子-β信号是否可以作为预防视网膜病变的治疗靶点，我们使用了一种药理学方法(SM16，1型转化生长因子-β受体激活素受体样激酶5的选择性抑制剂，口服活性)来抑制糖尿病大鼠视网膜血管中增加的，而不是基础的转化生长因子-β信号。在血管基因表达水平上，糖尿病3.5个月引起的变化很小。糖尿病+SM16治疗3周会引起广泛的基因表达变化，可能会增加血管炎症、血栓形成、渗漏和室壁不稳定；在服用SM16的对照组大鼠中没有观察到这些变化。在肺中未观察到糖尿病和SM16在改变基因表达方面的协同作用。在血管网络形态的水平上，7个月的糖尿病没有引起明显的变化。糖尿病+SM16治疗3周后，形态发生改变，密度降低。因此，在糖尿病中，视网膜血管依赖于通过激活素受体样激酶5小幅增加的转化生长因子-β信号来维持早期的完整性。增加的转化生长因子-β信号可能防止视网膜病变的快速进展，不应成为抑制性干预的目标。
The roles of transforming growth factor (TGF)-beta in extracellular matrix production and vascular remodeling, coupled with increased TGF-beta expression and signaling in diabetes, suggest TGF-beta as an important contributor to the microangiopathy of diabetic retinopathy and nephropathy. To investigate whether increased TGF-beta signaling could be a therapeutic target for preventing retinopathy, we used a pharmacologic approach (SM16, a selective inhibitor of the type 1 TGF-beta receptor activin receptor-like kinase 5, orally active) to inhibit the increased, but not the basal, Tgf-beta signaling in retinal vessels of diabetic rats. At the level of vascular gene expression, 3.5 months' diabetes induced minimal changes. Diabetes + SM16 for 3 weeks caused widespread changes in gene expression poised to enhance vascular inflammation, thrombosis, leakage, and wall instability; these changes were not observed in control rats given SM16. The synergy of diabetes and SM16 in altering gene expression was not observed in the Lung. At the level of vascular network morphology, 7 months' diabetes induced no detectable changes. Diabetes + SM16 for 3 weeks caused instead distorted morphology and decreased density. Thus, in diabetes, retinal vessels become dependent on a small increase in TGF-beta signaling via activin receptor-like kinase 5 to maintain early integrity. The increased TGF-beta signaling may protect against rapid retinopathy progression and should not be a target of inhibitory interventions.