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Simvastatin preparations promote PDGF-BB secretion to repair LPS-induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway.

ABSTRACT: Endothelial barrier dysfunction is a critical pathophysiological process of sepsis. Impaired endothelial cell migration is one of the main reasons for endothelial dysfunction. Statins may have a protective effect on endothelial barrier function. However, the effect and mechanism of statins on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction remain unclear. Simvastatin (SV) was loaded in nanostructured lipid carriers to produce SV nanoparticles (SV-NPs). Normal SV and SV-NPs were used to treat human umbilical vein vascular endothelial cells (HUVECs) injured by LPS. Barrier function was evaluated by monitoring cell monolayer permeability and transendothelial electrical resistance, and cell migration ability was measured by a wound healing assay. LY294002 and imatinib were used to inhibit the activity of PI3K/Akt and platelet-derived growth factor receptor (PDGFR) β. IQ-GTPase-activating protein 1 (IQGAP1) siRNA was used to knockdown endogenous IQGAP1, which was used to verify the role of the PDGFRβ/PI3K/Akt/IQGAP1 pathway in SV/SV-NPs-mediated barrier protection in HUVECs injured by LPS. The results show that SV/SV-NPs promoted the migration and decreased the permeability of HUVECs treated with LPS, and the efficacy of the SV-NPs exceeded that of SV significantly. LY294002, imatinib and IQGAP1 siRNA all suppressed the barrier protection of SV/SV-NPs. SV/SV-NPs promoted the secretion of platelet-derived growth factor-BB (PDGF-BB) and activated the PDGFRβ/PI3K/Akt/IQGAP1 pathway. SV preparations restored endothelial barrier function by restoring endothelial cell migration, which is involved in the regulation of the PDGFRβ/PI3K/Akt/IQGAP1 pathway and PDGF-BB secretion. As an appropriate formulation for restoring endothelial dysfunction, SV-NPs may be more effective than SV.

SUBMITTER: Zheng X

PROVIDER: S-EPMC6850957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFibrotic scar formation and inflammation are characteristic pathologies of spinal cord injury (SCI) in the injured core, which has been widely regarded as the main barrier to axonal regeneration resulting in permanent functional recovery failure. Pericytes were shown to be the main source of fibroblasts that form fibrotic scar. However, the mechanism of pericyte-fibroblast transition after SCI remains elusive.MethodsFibrotic scarring and microvessels were assessed using immunofluorescence staining after establishing a crush SCI model. To study the process of pericyte-fibroblast transition, we analyzed pericyte marker and fibroblast marker expression using immunofluorescence. The distribution and cellular origin of platelet-derived growth factor (PDGF)-BB were examined with immunofluorescence. Pericyte-fibroblast transition was detected with immunohistochemistry and Western blot assays after PDGF-BB knockdown and blocking PDGF-BB/PDGFRβ signaling in vitro. Intrathecal injection of imatinib was used to selectively inhibit PDGF-BB/PDGFRβ signaling. The Basso mouse scale score and footprint analysis were performed to assess functional recovery. Subsequently, axonal regeneration, fibrotic scarring, fibroblast population, proliferation and apoptosis of PDGFRβ+ cells, microvessel leakage, and the inflammatory response were assessed with immunofluorescence.ResultsPDGFRβ+ pericytes detached from the blood vessel wall and transitioned into fibroblasts to form fibrotic scar after SCI. PDGF-BB was mainly distributed in the periphery of the injured core, and microvascular endothelial cells were one of the sources of PDGF-BB in the acute phase. Microvascular endothelial cells induced pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway in vitro. Pharmacologically blocking the PDGF-BB/PDGFRβ pathway promoted motor function recovery and axonal regeneration and inhibited fibrotic scar formation. After fibrotic scar formation, blocking the PDGFRβ receptor inhibited proliferation and promoted apoptosis of PDGFRβ+ cells. Imatinib did not alter pericyte coverage on microvessels, while microvessel leakage and inflammation were significantly decreased after imatinib treatment.ConclusionsWe reveal that the crosstalk between microvascular endothelial cells and pericytes promotes pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway. Our finding suggests that blocking the PDGF-BB/PDGFRβ signaling pathway with imatinib contributes to functional recovery, fibrotic scarring, and inflammatory attenuation after SCI and provides a potential target for the treatment of SCI.

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Simvastatin preparations promote PDGF-BB secretion to repair LPS-induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway.

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