Dagher Zeina, Gerhardinger Chiara, Vaz Joseph, Goodridge Michael, Tecilazich Francesco, Lorenzi Mara
Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts.
Am J Pathol. 2017 Mar;187(3):627-638. doi: 10.1016/j.ajpath.2016.11.007. Epub 2017 Feb 2.
The roles of transforming growth factor (TGF)-β in extracellular matrix production and vascular remodeling, coupled with increased TGF-β expression and signaling in diabetes, suggest TGF-β as an important contributor to the microangiopathy of diabetic retinopathy and nephropathy. To investigate whether increased TGF-β signaling could be a therapeutic target for preventing retinopathy, we used a pharmacologic approach (SM16, a selective inhibitor of the type 1 TGF-β receptor activin receptor-like kinase 5, orally active) to inhibit the increased, but not the basal, Tgf-β 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-β signaling via activin receptor-like kinase 5 to maintain early integrity. The increased TGF-β signaling may protect against rapid retinopathy progression and should not be a target of inhibitory interventions.
转化生长因子（TGF）-β在细胞外基质产生和血管重塑中的作用，以及糖尿病中TGF-β表达和信号传导的增加，表明TGF-β是糖尿病视网膜病变和肾病微血管病变的重要促成因素。为了研究增加的TGF-β信号传导是否可能成为预防视网膜病变的治疗靶点，我们采用了一种药理学方法（SM16，一种口服活性的1型TGF-β受体激活素受体样激酶5的选择性抑制剂）来抑制糖尿病大鼠视网膜血管中增加的但非基础的Tgf-β信号传导。在血管基因表达水平上，3.5个月的糖尿病仅引起微小变化。糖尿病 + SM16处理3周导致基因表达发生广泛变化，这些变化可能会增强血管炎症、血栓形成、渗漏和血管壁不稳定性；在给予SM16的对照大鼠中未观察到这些变化。糖尿病和SM16在改变基因表达方面的协同作用在肺部未观察到。在血管网络形态水平上，7个月的糖尿病未引起可检测到的变化。糖尿病 + SM16处理3周反而导致形态扭曲和密度降低。因此，在糖尿病中，视网膜血管变得依赖于通过激活素受体样激酶5的TGF-β信号传导的小幅增加来维持早期完整性。增加的TGF-β信号传导可能有助于防止视网膜病变的快速进展，不应成为抑制性干预的靶点。
