Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: implication of miRNAs and microvesicles

Zi-Sen Zhang; Yi-Yan Liu; Shuang-Shuang He; Dai-Qin Bao; Hong-Chen Wang; Jie Zhang; Xiao-Yong Peng; Jia-Tao Zang; Yu Zhu; Yue Wu; Qing-Hui Li; Tao Li; Liang-Ming Liu

doi:10.1186/s40779-023-00442-2

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Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: implication of miRNAs and microvesicles

RESEARCH | Updated：2025-12-13

- Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: implication of miRNAs and microvesicles
- Military Medical Research Vol. 11, Issue 1, Pages: 1-18(2024)
- Affiliations：
  
  State Key Laboratory of Trauma, Burns and Combined Injury, Department of Shock and Transfusion, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China
- Author bio：
  
  * lt200132@tmmu.edu.cn;
  lmliu62@tmmu.edu.cn
- Funds：
- DOI：10.1186/s40779-023-00442-2
  CLC：
- Published：2024-02
- Accepted：
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Cite this article as: Zhang ZS, Liu YY, He SS, Bao DQ, Wang HC, Zhang J, et al. Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: implication of miRNAs and microvesicles. Mil Med Res. 2023;10(1):13.
DOI：

Cite this article as: Zhang ZS, Liu YY, He SS, Bao DQ, Wang HC, Zhang J, et al. Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: implication of miRNAs and microvesicles. Mil Med Res. 2023;10(1):13. 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-β (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 (

0.05). Transplantation with exogenous pericytes protected vascular reactivity and barrier function

via

microvessel colonization (

0.05). Cx43 knockout in either pericytes or VECs reduced pericyte colonization in microvessels (

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 (

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.

关键词

Keywords

references

Yao YM , Zhang H . Better therapy for combat injury . Mil Med Res . 2019 ; 6 ( 1 ): 23 .

Singh V , Akash R , Chaudhary G , Singh R , Choudhury S , Shukla A , et al . Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice . Sci Rep . 2022 ; 12 ( 1 ): 2941 .

Ince C , Mayeux PR , Nguyen T , Gomez H , Kellum JA , Ospina-Tascon GA , et al . The endothelium in sepsis . Shock . 2016 ; 45 ( 3 ): 259 – 70 .

Auriemma CL , Zhuo H , Delucchi K , Deiss T , Liu T , Jauregui A , et al . Acute respiratory distress syndrome-attributable mortality in critically ill patients with sepsis . Intensive Care Med . 2020 ; 46 ( 6 ): 1222 – 31 .

Senatore F , Balakumar P , Jagadeesh G . Dysregulation of the renin-angiotensin system in septic shock: mechanistic insights and application of angiotensin Ⅱ in clinical management . Pharmacol Res . 2021 ; 174 : 105916 .

Gauer R , Forbes D , Boyer N . Sepsis: diagnosis and management . Am Fam Physician . 2020 ; 101 ( 7 ): 409 – 18 .

Dalkara T . Pericytes: a novel target to improve success of recanalization therapies . Stroke . 2019 ; 50 ( 10 ): 2985 – 91 .

Litvinukova M , Talavera-Lopez C , Maatz H , Reichart D , Worth CL , Lindberg EL , et al . Cells of the adult human heart . Nature . 2020 ; 588 ( 7838 ): 466 – 72 .

Meng YM , Jiang X , Zhao X , Meng Q , Wu S , Chen Y , et al . Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities . Nat Commun . 2021 ; 12 ( 1 ): 6011 .

Park SW , Yun JH , Kim JH , Kim KW , Cho CH , Kim JH . Angiopoietin 2 induces pericyte apoptosis via α3β1 integrin signaling in diabetic retinopathy . Diabetes . 2014 ; 63 ( 9 ): 3057 – 68 .

Yuan K , Agarwal S , Chakraborty A , Condon DF , Patel H , Zhang S , et al . Lung pericytes in pulmonary vascular physiology and pathophysiology . Compr Physiol . 2021 ; 11 ( 3 ): 2227 – 47 .

Castro Dias M , Mapunda JA , Vladymyrov M , Engelhardt B . Structure and junctional complexes of endothelial, epithelial and glial brain barriers . Int J Mol Sci . 2019 ; 20 ( 21 ): 5372 .

Ayloo S , Lazo CG , Sun S , Zhang W , Cui B , Gu C . Pericyte-to-endothelial cell signaling via vitronectin-integrin regulates blood-CNS barrier . Neuron . 2022 ; 110 ( 10 ): 1641 - 55.e6 .

Al Ahmad A , Taboada CB , Gassmann M , Ogunshola OO . Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult . J Cereb Blood Flow Metab . 2011 ; 31 ( 2 ): 693 – 705 .

Liu C , Ge HM , Liu BH , Dong R , Shan K , Chen X , et al . Targeting pericyteendothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction . Proc Natl Acad Sci U S A . 2019 ; 116 ( 15 ): 7455 – 64 .

Avolio E , Katare R , Thomas AC , Caporali A , Schwenke D , Carrabba M , et al . Cardiac pericyte reprogramming by MEK inhibition promotes arteriologenesis and angiogenesis of the ischemic heart . J Clin Invest . 2022 ; 132 ( 10 ): e152308 .

Kisler K , Nelson AR , Rege SV , Ramanathan A , Wang Y , Ahuja A , et al . Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain . Nat Neurosci . 2017 ; 20 ( 3 ): 406 – 16 .

Abed A , Toubas J , Kavvadas P , Authier F , Cathelin D , Alfieri C , et al . Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice . Kidney Int . 2014 ; 86 ( 4 ): 768 – 79 .

Nishii K , Seki A , Kumai M , Morimoto S , Miwa T , Hagiwara N , et al . Connexin45 contributes to global cardiovascular development by establishing myocardial impulse propagation . Mech Dev . 2016 ; 140 : 41 – 52 .

Chintalgattu V , Rees ML , Culver JC , Goel A , Jiffar T , Zhang J , et al . Coronary microvascular pericytes are the cellular target of sunitinib malateinduced cardiotoxicity . Sci Transl Med . 2013 ; 5 ( 187 ): 187 – 269 .

Rittirsch D , Huber-Lang MS , Flierl MA , Ward PA . Immunodesign of experimental sepsis by cecal ligation and puncture . Nat Protoc . 2009 ; 4 ( 1 ): 31 – 6 .

Nishiguchi T , Cho K , Isaka S , Ueno M , Jin JO , Yamaguchi K , et al . Protective effect of porphyran isolated from discolored nori (Porphyra yezoensis) on lipopolysaccharide-induced endotoxin shock in mice . Int J Biol Macromol . 2016 ; 93 ( Pt A ): 1273 – 8 .

Liu G , Meng C , Pan M , Chen M , Deng R , Lin L , et al . Isolation, purification, and cultivation of primary retinal microvascular pericytes: a novel model using rats . Microcirculation . 2014 ; 21 ( 6 ): 478 – 89 .

Duan C , Wang L , Zhang J , Xiang X , Wu Y , Zhang Z , et al . Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity . Redox Biol . 2020 ; 37 : 101706 .

Gaceb A , Ozen I , Padel T , Barbariga M , Paul G . Pericytes secrete proregenerative molecules in response to platelet-derived growth factor-BB . J Cereb Blood Flow Metab . 2018 ; 38 ( 1 ): 45 – 57 .

Jung MK , Mun JY . Sample preparation and imaging of exosomes by transmission electron microscopy . J Vis Exp . 2018 ; 131 : 56482 .

Wang Y , Zhang L , Li Y , Chen L , Wang X , Guo W , et al . Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium . Int J Cardiol . 2015 ; 192 : 61 – 9 .

Zhang J , Yang G , Zhu Y , Peng X , Li T , Liu L . Relationship of Cx43 regulation of vascular permeability to osteopontin-tight junction protein pathway after sepsis in rats . Am J Physiol Regul Integr Comp Physiol . 2018 ; 314 ( 1 ): R1 – 11 .

Yang G , Li T , Xu J , Liu L . PKC plays an important mediated effect in arginine vasopressin induced restoration of vascular responsiveness and calcium sensitization following hemorrhagic shock in rats . Eur J Pharmacol . 2010 ; 628 ( 1–3 ): 148 – 54 .

Jing H , Zhang X , Luo K , Luo Q , Yin M , Wang W , et al . miR-381-abundant small extracellular vesicles derived from kartogenin-preconditioned mesenchymal stem cells promote chondrogenesis of MSCs by targeting TAOK1 . Biomaterials . 2020 ; 231 : 119682 .

Zhou H , Zheng D , Wang H , Wu Y , Peng X , Li Q , et al . The protective effects of pericyte-derived microvesicles on vascular endothelial functions via CTGF delivery in sepsis . Cell Commun Signal . 2021 ; 19 ( 1 ): 115 .

Singer M , Deutschman CS , Seymour CW , Shankar-Hari M , Annane D , Bauer M , et al . The third international consensus definitions for sepsis and septic shock (Sepsis-3) . JAMA . 2016 ; 315 ( 8 ): 801 – 10 .

Li Z , Yin M , Zhang H , Ni W , Pierce RW , Zhou HJ , et al . BMX represses thrombin-PAR1-mediated endothelial permeability and vascular leakage during early sepsis . Circ Res . 2020 ; 126 ( 4 ): 471 – 85 .

Joffre J , Hellman J , Ince C , Ait-Oufella H . Endothelial responses in sepsis . Am J Respir Crit Care Med . 2020 . https://doi.org/10.1164/rccm.201910-1911TR https://doi.org/10.1164/rccm.201910-1911TR .

Munroe M , Dvoretskiy S , Lopez A , Leong J , Dyle MC , Kong H , et al . Pericyte transplantation improves skeletal muscle recovery following hindlimb immobilization . FASEB J . 2019 ; 33 ( 6 ): 7694 – 706 .

Alvino VV , Fernández-Jiménez R , Rodriguez-Arabaolaza I , Slater S , Mangialardi G , Avolio E , et al . Transplantation of allogeneic pericytes improves myocardial vascularization and reduces interstitial fibrosis in a swine model of reperfused acute myocardial infarction . J Am Heart Assoc . 2018 ; 7 ( 2 ): e006727 .

Konig MA , Canepa DD , Cadosch D , Casanova E , Heinzelmann M , Rittirsch D , et al . Direct transplantation of native pericytes from adipose tissue: a new perspective to stimulate healing in critical size bone defects . Cytotherapy . 2016 ; 18 ( 1 ): 41 – 52 .

Alarcon-Martinez L , Villafranca-Baughman D , Quintero H , Kacerovsky JB , Dotigny F , Murai KK , et al . Interpericyte tunnelling nanotubes regulate neurovascular coupling . Nature . 2020 ; 585 ( 7823 ): 91 – 5 .

Medina-Flores F , Hurtado-Alvarado G , Contis-Montes De Oca A , Lopez-Cervantes SP , Konigsberg M , Deli MA , et al . Sleep loss disrupts pericytebrain endothelial cell interactions impairing blood–brain barrier function . Brain Behav Immun . 2020 ; 89 : 118 – 32 .

Katare R , Riu F , Mitchell K , Gubernator M , Campagnolo P , Cui Y , et al . Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132 . Circ Res . 2011 ; 109 ( 8 ): 894 – 906 .

Wu Y , Li P , Goodwin AJ , Cook JA , Halushka PV , Zingarelli B , et al . miR-145a regulation of pericyte dysfunction in a murine model of sepsis . J Infect Dis . 2020 ; 222 ( 6 ): 1037 – 45 .

Chin DD , Poon C , Wang J , Joo J , Ong V , Jiang Z , et al . miR-145 micelles mitigate atherosclerosis by modulating vascular smooth muscle cell phenotype . Biomaterials . 2021 ; 273 : 120810 .

Xu B , Zhang Y , Du XF , Li J , Zi HX , Bu JW , et al . Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity . Cell Res . 2017 ; 27 ( 7 ): 882 – 97 .

Cartier A , Leigh T , Liu CH , Hla T . Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy . Proc Natl Acad Sci U S A . 2020 ; 117 ( 6 ): 3157 – 66 .

Abdel Rahman F , D’almeida S , Zhang T , Asadi M , Bozoglu T , Bongiovanni D , et al . Sphingosine-1-phosphate attenuates lipopolysaccharideinduced pericyte loss via activation of Rho-A and MRTF-A . Thromb Haemost . 2021 ; 121 ( 3 ): 341 – 50 .

Hubner K , Cabochette P , Dieguez-Hurtado R , Wiesner C , Wakayama Y , Grassme KS , et al . Wnt/β-catenin signaling regulates VE-cadherin-mediated anastomosis of brain capillaries by counteracting S1pr1 signaling . Nat Commun . 2018 ; 9 ( 1 ): 4860 .

Hoefer J , Azam MA , Kroetsch JT , Leong-Poi H , Momen MA , Voigtlaender-Bolz J , et al . Sphingosine-1-phosphate-dependent activation of p38 MAPK maintains elevated peripheral resistance in heart failure through increased myogenic vasoconstriction . Circ Res . 2010 ; 107 ( 7 ): 923 – 33 .

Lee JF , Gordon S , Estrada R , Wang L , Siow DL , Wattenberg BW , et al . Balance of S1P1 and S1P2 signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature . Am J Physiol Heart Circ Physiol . 2009 ; 296 ( 1 ): H33 - 42 .

Park SJ , Kim JM , Kim J , Hur J , Park S , Kim K , et al . Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns . Proc Natl Acad Sci U S A . 2018 ; 115 ( 50 ): E11721 – 30 .

Deng L , Li H , Su X , Zhang Y , Xu H , Fan L , et al . Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation . Cell Death Dis . 2020 ; 11 ( 3 ): 158 .

Evaristo-Mendonca F , Sardella-Silva G , Kasai-Brunswick TH , Campos RMP , Domizi P , Santiago MF , et al . Preconditioning of rat bone marrow-derived mesenchymal stromal cells with Toll-like receptor agonists . Stem Cells Int . 2019 ; 2019 : 7692973 .

Zhao X , Liu D , Gong W , Zhao G , Liu L , Yang L , et al . The Toll-like receptor 3 ligand, poly(I:C), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting MiR-143 . Stem Cells . 2014 ; 32 ( 2 ): 521 – 33 .

Park J , Kim S , Lim H , Liu A , Hu S , Lee J , et al . Therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severe E . coli pneumonia. Thorax . 2019 ; 74 ( 1 ): 43 – 50 .

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