Cappellari Roberta, D'Anna Marianna, Menegazzo Lisa, Bonora Benedetta Maria, Albiero Mattia, Avogaro Angelo, Fadini Gian Paolo
Veneto Institute of Molecular Medicine, Padova, Italy.
Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy.
Diabetologia. 2020 Sep;63(9):1872-1884. doi: 10.1007/s00125-020-05142-3. Epub 2020 Apr 18.
AIMS/HYPOTHESIS: Cardiovascular risk in diabetes is at least in part attributable to defective angiogenesis. Since diabetes negatively affects blood cells involved in angiogenesis, we herein evaluated whether diabetes impairs proangiogenic granulocytes (PAGs).
We characterised and quantified PAGs as CD49d granulocytes in peripheral blood of participants with type 2 or type 1 diabetes and in non-diabetic control participants. We evaluated PAG antigenic profile and assessed in vitro functional properties of CD49d granulocytes using 2D and 3D angiogenesis assays. We also quantified PAGs before and after glucose control with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin. In parallel, we measured Ly6GCD49d PAGs in streptozotocin-induced type 1-like diabetic mice vs non-diabetic control mice.
PAGs were composed of eosinophils (>80%) and neutrophils (<20%). Within both populations, CD49d identified CXCR4/VEGFR1 cells. CD49d granulocytes supported in vitro angiogenesis by endothelial cells significantly more than CD49d control granulocytes, and physically interacted with endothelial cells. Granulocytes from type 2 diabetic participants had a profoundly impaired capacity to stimulate endothelial cell tubule formation compared with those from non-diabetic control participants. CD49d PAGs were reduced by 30-40% and were functionally impaired in diabetic vs control individuals. PAG levels inversely correlated with plasma glucose (r = -0.25; p = 0.025) and significantly increased 1.8-times after glucose control with dapagliflozin, which reduced HbA by 1.0% (11 mmol/mol). Levels of Ly6GCD49d PAGs were also significantly reduced also in type 1 diabetic mice vs control mice.
CONCLUSIONS/INTERPRETATION: We illustrate a significant impairment of PAGs in diabetes and provide evidence for a direct role of hyperglycaemia. These findings add mechanistic information to explain the defective angiogenesis in diabetes. Graphical abstract.
目的/假设：糖尿病中的心血管风险至少部分归因于血管生成缺陷。由于糖尿病会对参与血管生成的血细胞产生负面影响，我们在此评估糖尿病是否会损害促血管生成粒细胞（PAGs）。
我们将PAGs鉴定并定量为2型或1型糖尿病患者以及非糖尿病对照参与者外周血中的CD49d粒细胞。我们评估了PAG的抗原谱，并使用二维和三维血管生成试验评估了CD49d粒细胞的体外功能特性。我们还使用钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂达格列净在血糖控制前后对PAGs进行了定量。同时，我们测量了链脲佐菌素诱导的1型糖尿病样小鼠与非糖尿病对照小鼠中Ly6G⁺CD49d⁺ PAGs的水平。
PAGs由嗜酸性粒细胞（>80%）和中性粒细胞（<20%）组成。在这两个群体中，CD49d识别出CXCR4/VEGFR1细胞。CD49d粒细胞比CD49d对照粒细胞更能显著支持内皮细胞的体外血管生成，并与内皮细胞发生物理相互作用。与非糖尿病对照参与者相比，2型糖尿病参与者的粒细胞刺激内皮细胞小管形成的能力严重受损。与对照个体相比，糖尿病患者的CD49d PAGs减少了30%-40%，并且功能受损。PAG水平与血浆葡萄糖呈负相关（r = -0.25；p = 0.025），在用达格列净控制血糖后显著增加了1.8倍，达格列净使糖化血红蛋白降低了1.0%（11 mmol/mol）。1型糖尿病小鼠中的Ly6G⁺CD49d⁺ PAGs水平也比对照小鼠显著降低。
结论/解读：我们阐明了糖尿病中PAGs的显著损伤，并为高血糖的直接作用提供了证据。这些发现增加了解释糖尿病中血管生成缺陷的机制信息。图形摘要。
