The protective effects of pericyte-derived microvesicles on vascular endothelial functions via CTGF delivery in
Henan Zhou1, Danyang Zheng1,2, Hongchen Wang1
1State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Army Medical Center of PLA, Daping Hospital, Army Medical University, No.10th Daping Changjiang Road, Chongqing, 400038, China.
Background:
It is well known that sepsis is a prevalent severe disease caused by infection and the treatment strategies are limited. Recently pericyte-derived microvesicles (PMVs) were confirmed to be therapeutic in many diseases, whether PMVs can protect vascular endothelial cell (VEC) injury is unknown.
Methods:
Pericytes were extracted from the retina of newly weaned rats, and PMVs were collected after starvation and characterized by flow-cytometry and transmission electron microscopy. First, the effect of PMVs on pulmonary vascular function in septic rats was measured via intravenous administration with HE staining, immunofluorescence, and Elisa analysis. Then, PMVs were co-incubated with VECs in the presence of lipopolysaccharide (LPS), and observed the protective effect of PMVs on VECs. Next, the proteomic analysis and further Gene Ontology (GO) enrichment analysis were performed to analyze the therapeutic mechanism of PMVs, and the angiogenesis-related protein CTGF was highly expressed in PMVs. Finally, by CTGF upregulation and downregulation in PMV, the role of PMV-carried CTGF was investigated.
Results:
PMVs restored the proliferation and angiogenesis ability of pulmonary VECs, and alleviated pulmonary vascular leakage in septic rats and LPS-stimulated VECs. Further study showed that PMVs delivered CTGF to VECs, and subsequently activated ERK1/2, and increased the phosphorylation of STAT3, thereby improving the function of VECs. The further study found CD44 mediated the absorption and internalization of PMVs to VECs, the anti-CD44 antibody inhibited the protective effect of PMVs.
Conclusions:
PMVs may delivery CTGF to VECs, and promote the proliferation and angiogenesis ability by activating the CTGF-ERK1/2-STAT3 axis, thereby protecting pulmonary vascular function in sepsis. The therapeutic effect of PMVs was highly related to CD44-mediated absorption. Video Abstract.
Insights
Pericyte-derived microvesicles (PMVs) protect against sepsis-induced vascular injury by delivering CTGF to endothelial cells. This process, mediated by CD44, restores vascular function and proliferation, offering a novel therapeutic avenue.
Area of Science:
- Biomedical research
- Cell biology
- Vascular biology
Background:
- Sepsis is a life-threatening condition with limited treatment options.
- Vascular endothelial cell (VEC) injury is a critical component of sepsis.
- Pericyte-derived microvesicles (PMVs) show therapeutic potential, but their effect on VEC injury is unknown.
Purpose of the Study:
- To investigate the protective effects of PMVs on VEC injury in sepsis.
- To elucidate the underlying therapeutic mechanisms of PMVs.
- To determine the role of CTGF and CD44 in PMV-mediated protection.
Main Methods:
- PMVs were isolated from rat retinas and characterized.
- Septic rats and LPS-stimulated VECs were used to assess PMV efficacy.
- Proteomic and Gene Ontology analyses identified key molecular pathways.
- CTGF modulation and CD44 inhibition were employed to study mechanisms.
Main Results:
- PMVs restored pulmonary VEC proliferation and angiogenesis.
- PMVs alleviated vascular leakage in septic rats and LPS-treated VECs.
- PMVs delivered CTGF to VECs, activating the ERK1/2-STAT3 pathway.
- CD44 mediated PMV uptake by VECs, essential for their protective effect.
Conclusions:
- PMVs protect against sepsis-induced pulmonary vascular injury.
- The mechanism involves CTGF delivery to VECs, activating the CTGF-ERK1/2-STAT3 axis.
- CD44-mediated uptake is crucial for the therapeutic efficacy of PMVs.
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