周细胞
壁细胞
血管通透性
败血症
血管平滑肌
医学
微泡
炎症
免疫学
药理学
细胞生物学
生物
内皮干细胞
体外
病理
小RNA
内科学
生物化学
平滑肌
基因
作者
Zisen Zhang,Yi-Yan Liu,Shuangshuang He,Daiqin Bao,Hongchen Wang,Jie Zhang,Xiaotong Peng,Jiatao Zang,Yu Zhu,Yuzhang Wu,Qing-Hui Li,Tao Li,Liangming Liu
标识
DOI:10.1186/s40779-023-00442-2
摘要
Abstract Background 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. Methods 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 + Cx43 flox/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. Results 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. Conclusions Pericytes are protective against sepsis through regulating vascular reactivity and barrier function. Possible mechanisms include both direct colonization of microvasculature and secretion of PCMVs.
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