鞘氨醇激酶-磷酸鞘氨醇轴在血管生成相关性疾病中的作用

The Role of SPHK-S1P Axis in Angiogenesis-related Diseases

血管生成是指在原有血管的基础上形成新血管的过程。病理性血管生成是癌症、心血管类疾病和视网膜病变等一系列疾病的标志。1-磷酸鞘氨醇(sphingosine-1-phosphate, S1P)是一种信号脂质,由鞘氨醇激酶(sphingosine kinases, SPHK)合成,通过5种G蛋白偶联受体(sphingosine-1-phosphate receptors, S1PR1-5)发挥其不同的生物学和病理生理作用,并通过激活受体启动各种信号级联反应,影响细胞命运、血管张力、内皮功能和完整性以及淋巴细胞的运输等。其产生和信号的失衡与内皮功能障碍和异常血管生成等病理过程密切相关。越来越多的证据表明,SPHK-S1P轴在血管生成中发挥重要作用,尤其在癌症的发生发展与肿瘤微环境、动脉粥样硬化、心肌梗死等心血管类疾病,以及糖尿病和视网膜病变中具有重要意义。研究其相关作用与功能,可为治疗血管生成相关疾病提供新见解和药物治疗靶点。本文就SPHK-S1P轴通过SPHK以及S1PR1-5影响内皮细胞和平滑肌增殖、内皮细胞迁移以及由内皮细胞、周细胞和平滑肌细胞等形成管腔的分子机制进行阐述,同时进一步阐述SPHK-S1P轴如何通过鞘氨醇激酶以及S1PR1-5影响肿瘤、心血管类疾病、糖尿病以及视网膜病变中血管生成,旨在通过理解SPHK-S1P轴在血管生成中的分子机制为相关疾病提供新的治疗思路。

Angiogenesis refers to the process of forming new blood vessels based on original blood vessels. Pathological angiogenesis is a sign of a series of diseases such as cancer, cardiovascular diseases, and retinopathy. Sphingosine 1-phosphate(S1 P) is a signaling lipid synthesized by sphingosine kinase(SPHK) that exerts its diverse biological and pathophysiological roles through five G protein-coupled receptors(S1 PR1-5) and initiates various signaling cascades by activating receptors that affect cell fate, vascular tension, endothelial function and integrity, and lymphocyte transport. The imbalance ofproduction and signal is closely related to pathological processes such as endothelial dysfunction and abnormal angiogenesis. Accumulating evidence suggests that the SPHK-S1 P axis plays an important role in angiogenesis, especially in the development of tumors, diabetes retinopathy, atherosclerosis, myocardial infarction and other cardiovascular diseases. Studies on its roles and functions can provide new insights and drug therapeutic targets for the treatment of angiogenesis-related diseases.This review describes the molecular mechanisms by which the SPHK-S1 P axis affects endothelial cell and smooth muscle cellproliferation, endothelial cell migration and the formation of lumen by endothelial cells, pericytes and smooth muscle cells through SPHK and S1 PR1-5. The review also elaborates how the SPHK-S1 P axis affects angiogenesis in tumors, cardiovascular diseases, diabetes and retinopathy through SPHK and S1 PR1-5, and aims to provide new therapeutic strategy for related diseases by understanding the molecular mechanism of the SPHK-S1 P axis in angiogenesis.