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Programming to S1PR1+ Endothelial Cell Promotes Restoration of Lung Vascular Integrity

ABSTRACT: Programming to S1PR1+ Endothelial Cell Promotes Restoration of Lung Vascular Integrity

PROVIDER: PRJNA692749 | ENA |

REPOSITORIES: ENA

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Programming to S1PR1+ Endothelial Cell Promotes Restoration of Lung Vascular Integrity

Project description:Increased endothelial permeability and failure to repair is the hallmark of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways that activate endothelial cell (EC) regenerative programs and thereby tissue repair. Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1). Here, we addressed mechanisms of generation of S1PR1+ EC, which may prevent endothelial injury. Studies were made using inducible EC-S1PR1-/- (iEC-S1PR1-/-) mice and S1PR1-GFP reporter mice to trace the generation of S1PR1+ EC. We observed in a mouse model of endotoxemia that S1P generation induced the programming of S1PR1lo to S1PR1+ EC, which comprised 80% of lung EC. The transition of these cells was required for reestablishing the endothelial barrier. We also observed that conditional deletion of S1PR1 in EC increased vascular permeability. RNA-seq analysis of S1PR1+ EC showed enrichment of genes regulating S1P synthesis and transport, sphingosine kinase 1 (SPHK1) and SPNS2, respectively. The activation of transcription factors EGR1 and STAT3 were essential for transcribing SPHK1 and SPNS2, respectively, to increase S1P production that served to amplify S1PR1+ EC transition. Transplantation of S1PR1+ EC into injured lung vasculature restored endothelial integrity. Our findings show that generation of a S1PR1+ EC population activates the endothelial regenerative program mediating vascular endothelial repair, thus raising the possibility of harnessing this pathway to restore vascular homeostasis in inflammatory injury.

2023-01-15 | GSE165000 | GEO

Programming to S1PR1<sup>+</sup> Endothelial Cells Promotes Restoration of Vascular Integrity.

Project description:[Figure: see text].

| S-EPMC8273089 | biostudies-literature

PARP15 promotes vascular barrier integrity in inflammation

Project description:PARP15 promotes vascular barrier integrity in inflammation

| PRJNA989163 | ENA

TRAF7 is an essential regulator of vascular integrity

Project description:TRAF7 is an essential regulator of vascular integrity

| PRJNA955312 | ENA

Vascular integrity is essential for maintaining tissue homeostasis

Project description:Vascular integrity is essential for maintaining tissue homeostasis

| PRJNA681585 | ENA

Vascular integrity is essential for maintaining tissue homeostasis

Project description:Vascular integrity is essential for maintaining tissue homeostasis

| PRJNA857461 | ENA

Vascular integrity is essential for maintaining tissue homeostasis I

Project description:Vascular integrity is essential for maintaining tissue homeostasis I

| PRJNA681529 | ENA

Vascular integrity is essential for maintaining tissue homeostasis II

Project description:Vascular integrity is essential for maintaining tissue homeostasis II

| PRJNA681577 | ENA

Vascular integrity is essential for maintaining tissue homeostasis III

Project description:Vascular integrity is essential for maintaining tissue homeostasis III

| PRJNA681584 | ENA

Cardiomyocyte S1pr1 regulates cardiac regeneration via AKT/mTOR signaling pathway

Project description:Mammalian hearts had the capability to regenerate cardiomyocyte and completely recover after heart injury within a limited time window after birth. It has been shown that sphingosine 1-phospahte receptor 1 (S1pr1) was highly expressed in cardiomyocytes and played an important role in heart development and pathological cardiac remodeling. Herein, we aim to investigate the role of CM-S1pr1 for cardiac regeneration and tissue repair after heart injury. We generated cardiomyocyte (CM)-specific S1pr1 knock-out mice and showed that CM-specific S1pr1 loss-of-function significantly severely reduced cardiomyocyte proliferation and heart regeneration in neonatal mice after both apex resection and myocardial infarction, whereas S1pr1 gain-of-function by AAV9-mediated CM-specific overexpression of S1pr1 significantly boosted cardiac regeneration and improved cardiac functions after heart injuries. We next identified that S1pr1 activated AKT/mTOR/CyclinD1 and Bcl-2 signaling pathways, and thus promoted cardiomyocyte proliferation and inhibited CM apoptosis, respectively.Of note, we applied CM-targeted gene therapy by AAV9-cTNT to specifically overexpress S1pr1 in cardiomyocytes and achieved an efficient S1pr1 overexpression in CMs in vivo. This CM-targeted strategy to overexpress S1pr1 significantly enhanced cardiac regeneration and improved cardiac functions after myocardial infarction in an adult mouse model, suggesting a potential strategy to boost adult cardiac regeneration in vivo.

2024-08-01 | GSE241722 | GEO

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