Laboratories of Vascular Pathology and Regeneration, School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom.
Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):e149-60. doi: 10.1161/ATVBAHA.112.300497. Epub 2012 Oct 11.
The p75 neurotrophin receptor (p75(NTR)) contributes to diabetes mellitus-induced defective postischemic neovascularization. The interleukin-33 receptor ST2 is expressed as transmembrane (ST2L) and soluble (sST2) isoforms. Here, we studied the following: (1) the impact of p75(NTR) in the healing of ischemic and diabetic calf wounds; (2) the link between p75(NTR) and ST2; and (3) circulating sST2 levels in critical limb ischemia (CLI) patients.
Diabetes mellitus was induced in p75(NTR) knockout (p75KO) mice and wild-type (WT) littermates by streptozotocin. Diabetic and nondiabetic p75KO and WT mice received left limb ischemia induction and a full-thickness wound on the ipsilateral calf. Diabetes mellitus impaired wound closure and angiogenesis and increased ST2 expression in WT, but not in p75KO wounds. In cultured endothelial cells, p75(NTR) promoted ST2 (both isoforms) expression through p38(MAPK)/activating transcription factor 2 pathway activation. Next, sST2 was measured in the serum of patients with CLI undergoing either revascularization or limb amputation and in the 2 nondiabetic groups (with CLI or nonischemic individuals). Serum sST2 increased in diabetic patients with CLI and was directly associated with higher mortality at 1 year from revascularization.
p75(NTR) inhibits the healing of ischemic lower limb wounds in diabetes mellitus and promotes ST2 expression. Circulating sST2 predicts mortality in diabetic CLI patients.
p75 神经营养因子受体（p75（NTR））有助于糖尿病引起的缺血后血管新生缺陷。白细胞介素-33 受体 ST2 以跨膜（ST2L）和可溶性（sST2）两种形式表达。在这里，我们研究了以下内容：（1）p75（NTR）在缺血和糖尿病小腿伤口愈合中的作用；（2）p75（NTR）与 ST2 之间的联系；（3）临界肢体缺血（CLI）患者的循环 sST2 水平。
链脲佐菌素诱导 p75（NTR）敲除（p75KO）小鼠和野生型（WT）同窝仔鼠发生糖尿病。糖尿病和非糖尿病 p75KO 和 WT 小鼠接受左肢体缺血诱导和同侧小腿全层伤口。糖尿病可损害伤口闭合和血管生成，并增加 WT 但不增加 p75KO 伤口中的 ST2 表达。在培养的内皮细胞中，p75（NTR）通过 p38（MAPK）/激活转录因子 2 通路激活促进 ST2（两种同工型）的表达。接下来，在接受血运重建或肢体截肢的 CLI 患者以及 2 个非糖尿病组（CLI 或非缺血个体）的血清中测量 sST2。CLI 合并糖尿病患者的血清 sST2 升高，并且与血运重建后 1 年的死亡率直接相关。
p75（NTR）抑制糖尿病下肢缺血性伤口的愈合，并促进 ST2 的表达。循环 sST2 可预测糖尿病 CLI 患者的死亡率。
