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Updated: Aug 7, 2025
Microperfusion Technique to Investigate Regulation of Microvessel Permeability in Rat Mesentery
Published on: September 12, 2015
Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function:
Zi-Sen Zhang1, Yi-Yan Liu1, Shuang-Shuang He1
1State 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.
Insights
Pericytes protect against sepsis by maintaining vascular integrity and function. These cells, along with their secreted microvesicles, offer protection through direct colonization and molecular signaling pathways.
Area of Science:
- Vascular Biology
- Sepsis Pathophysiology
- Cellular Mechanisms
Background:
- Sepsis leads to multi-organ damage due to vascular hyporeactivity and leakage.
- Pericytes, crucial for vascular integrity, were investigated for their protective role in sepsis.
Purpose of the Study:
- To determine the protective effects of pericytes against sepsis-induced vascular dysfunction.
- To elucidate the mechanisms by which pericytes regulate vascular reactivity and permeability.
Main Methods:
- In vivo studies using genetically modified mice (PDGFR-β-Cre mT/mG, Tie2-Cre Cx43flox/flox) and pericyte depletion in rats (CP-673451).
- In vitro experiments with cultured pericytes, vascular endothelial cells (VECs), and vascular smooth muscle cells (VSMCs).
- Analysis of pericyte-derived microvesicles (PCMVs) and microRNAs (miRNAs) in sepsis models.
Main Results:
- Sepsis induced pericyte loss, vascular hyporeactivity, and leakage.
- Exogenous pericytes and their colonization improved vascular function.
- Pericyte-derived microvesicles transferred miR-145 and miR-132, which modulated VSMC contractility and VEC barrier function via specific signaling pathways (Sphk2/S1PR1/MLC20 and Sphk2/S1PR2/ZO-1/VE-cadherin).
Conclusions:
- Pericytes are protective in sepsis by preserving vascular reactivity and barrier function.
- Mechanisms involve direct microvessel colonization and paracrine signaling via pericyte-derived microvesicles.
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 + 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.
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.
