Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: implication of miRNAs and microvesicles.
Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: implication of miRNAs and microvesicles.
复制标题
DOI：
10.1186/s40779-023-00442-2
复制
发表时间：
2023-03-13
影响因子：
21.1
通讯作者：
中科院分区：
文献类型：
--
作者：
血管低反应性和渗漏是脓毒症时引起多器官损害的重要病理生理特征。我们假设，周细胞是一组维持血管完整性和张力的多能细胞，通过调节血管的反应性和通透性，对脓毒症具有保护作用。我们利用野生型(WT)、血小板衍生生长因子受体β(PDGFR-β)-Cre + Mt/mg转基因小鼠和Tie2-Cre + Cx43Flox/Flox小鼠进行了一系列体内实验，以检测周细胞在盲肠结扎穿孔或脂多糖刺激诱导的脓毒症中的相对作用。在SD大鼠的另一组实验中，使用选择性PDGFR-β抑制剂CP-673451以40 mg/(kg·d)的剂量连续7天耗尽周细胞。用培养的周细胞、血管内皮细胞(VECs)和血管平滑肌细胞(VSMCs)进行力学研究。此外，还检测了周细胞和周细胞来源的微囊泡(PCMV)和候选miRNAs对血管反应性和屏障功能的影响。中草药和脂多糖可导致周细胞严重损伤/丢失、血管反应性降低和渗漏(P <； 0.05)。外源性周细胞移植通过微血管定植保护血管反应性和屏障功能(P <； 0.05)。周细胞和血管内皮细胞中Cx43基因敲除均可减少周细胞在微血管中的定植(P <； 005)。此外，PCMV将miR-145和miR-132分别转移到VSMC和VEC，对脓毒症后的血管反应性和屏障功能起到保护作用(P <； 0.05)。MIR-145主要通过激活Sphk2/S1PR受体(S1PR)1/肌球蛋白轻链20通路的磷酸化来改善VSMC的收缩反应，而miR-132通过激活Sphk2/S1PR2/zonula occludens-1和血管内皮-钙粘素通路有效地改善VEC的屏障功能。周细胞通过调节血管反应性和屏障功能对脓毒症具有保护作用。可能的机制包括微血管的直接定植和PCMV的分泌。网上版载有补充材料，可在10.1186/s40779-023-00442-2查阅。
Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon sepsis. We hypothesized that pericytes, a group of pluripotent cells that maintain vascular integrity and tension, are protective against sepsis via regulating vascular reactivity and permeability. We conducted a series of in vivo experiments using wild-type (WT), platelet-derived growth factor receptor beta (PDGFR-β)-Cre + mT/mG transgenic mice and Tie2-Cre + Cx43flox/flox mice to examine the relative contribution of pericytes in sepsis, either induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. In a separate set of experiments with Sprague–Dawley (SD) rats, pericytes were depleted using CP-673451, a selective PDGFR-β inhibitor, at a dosage of 40 mg/(kg·d) for 7 consecutive days. Cultured pericytes, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) were used for mechanistic investigations. The effects of pericytes and pericyte-derived microvesicles (PCMVs) and candidate miRNAs on vascular reactivity and barrier function were also examined. CLP and LPS induced severe injury/loss of pericytes, vascular hyporeactivity and leakage (P < 0.05). Transplantation with exogenous pericytes protected vascular reactivity and barrier function via microvessel colonization (P < 0.05). Cx43 knockout in either pericytes or VECs reduced pericyte colonization in microvessels (P < 0.05). Additionally, PCMVs transferred miR-145 and miR-132 to VSMCs and VECs, respectively, exerting a protective effect on vascular reactivity and barrier function after sepsis (P < 0.05). miR-145 primarily improved the contractile response of VSMCs by activating the sphingosine kinase 2 (Sphk2)/sphingosine-1-phosphate receptor (S1PR)1/phosphorylation of myosin light chain 20 pathway, whereas miR-132 effectively improved the barrier function of VECs by activating the Sphk2/S1PR2/zonula occludens-1 and vascular endothelial-cadherin pathways. Pericytes are protective against sepsis through regulating vascular reactivity and barrier function. Possible mechanisms include both direct colonization of microvasculature and secretion of PCMVs. The online version contains supplementary material available at 10.1186/s40779-023-00442-2.