Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
J Vasc Surg. 2011 Jun;53(6):1654-60.e2. doi: 10.1016/j.jvs.2011.02.019.
Impaired wound healing is a major complication associated with diabetes, involving a dysregulation and impairments in the inflammatory and angiogenic phases of wound healing. Here, we examine the effects of the neuropeptides substance P (SP) and neuropeptide Y (NPY) on dermal microvascular endothelial cell (DMVEC) angiogenesis and interleukin-8 (IL-8) expression, a known effector of the neuropeptide pathways in normal and hyperglycemic conditions in vitro.
DMVECs are treated with one of four glucose concentrations: 1) 5 mM glucose; 2) 10 mM glucose; 3) 30 mM glucose; or 4) 30 mM mannitol and cotreated with 100 nM NPY, 100 nM SP, or 10 ng/mL IL-8. Angiogenesis is assessed with proliferation and tube formation assays. IL-8 mRNA and protein expression are evaluated at days 1 and 7.
As compared with noromoglycemia (5 mM glucose), hyperglycemia (30 mM glucose) decreases DMVEC proliferation and tube formation by 39% and 42%, respectively. SP cotreatment restores DMVEC proliferation (211%) and tube formation (152%), and decreases IL-8 expression (34%) in DMVECs exposed to hyperglycemic conditions. These effects are not observed with NPY. However, IL-8 treatment by itself does not affect proliferation or tube formation, suggesting that the effect of SP on DMVEC angiogenesis is unlikely through changes in IL-8 expression.
Hyperglycemic conditions impair DMVEC proliferation and tube formation. SP mitigates the effect of hyperglycemia on DMVECs by increasing DMVEC proliferation and tube formation. These findings are not likely to be related to a dysregulation of IL-8 due to the lack of effects of hyperglycemia on IL-8 expression and the lack of effect of IL-8 on DMVEC proliferation and tube formation. The effect of SP on DMVECs makes SP a promising potential target for therapy in impaired wound healing in diabetes, but the exact mechanism remains unknown.
伤口愈合受损是糖尿病的主要并发症之一，涉及炎症和血管生成阶段的失调和受损。在这里，我们研究了神经肽物质 P（SP）和神经肽 Y（NPY）对真皮微血管内皮细胞（DMVEC）血管生成和白细胞介素-8（IL-8）表达的影响，IL-8 是正常和高血糖条件下神经肽途径的已知效应物。
用四种葡萄糖浓度之一处理 DMVEC：1）5mM 葡萄糖；2）10mM 葡萄糖；3）30mM 葡萄糖；或 4）30mM 甘露醇，并与 100nM NPY、100nM SP 或 10ng/mL IL-8 共同处理。通过增殖和管形成测定评估血管生成。第 1 天和第 7 天评估 IL-8mRNA 和蛋白表达。
与正常血糖（5mM 葡萄糖）相比，高血糖（30mM 葡萄糖）使 DMVEC 的增殖和管形成分别降低了 39%和 42%。SP 共处理恢复了高糖条件下 DMVEC 的增殖（211%）和管形成（152%），并降低了 DMVEC 的 IL-8 表达（34%）。NPY 则没有观察到这些作用。然而，IL-8 本身的治疗并不影响增殖或管形成，这表明 SP 对 DMVEC 血管生成的影响不太可能是通过改变 IL-8 的表达。
高血糖条件会损害 DMVEC 的增殖和管形成。SP 通过增加 DMVEC 的增殖和管形成来减轻高血糖对 DMVEC 的影响。由于高血糖对 IL-8 表达没有影响，以及 IL-8 对 DMVEC 的增殖和管形成没有影响，这些发现不太可能与 IL-8 的失调有关。SP 对 DMVEC 的作用使 SP 成为糖尿病受损伤口愈合治疗的有希望的潜在靶点，但确切机制尚不清楚。
