Malat1 deficiency prevents neonatal heart regeneration by inducing cardiomyocyte binucleation.

The adult mammalian heart has limited regenerative capacity, while the neonatal heart fully regenerates during the first week of life. Postnatal regeneration is mainly driven by proliferation of preexisting cardiomyocytes and supported by proregenerative macrophages and angiogenesis. Although the process of regeneration has been well studied in the neonatal mouse, the molecular mechanisms that define the switch between regenerative and nonregenerative cardiomyocytes are not well understood.

Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction.

Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing.

Biglycan evokes autophagy in macrophages via a novel CD44/Toll-like receptor 4 signaling axis in ischemia/reperfusion injury.

Biglycan, a small leucine-rich proteoglycan, acts as a danger signal and is classically thought to promote macrophage recruitment via Toll-like receptors (TLR) 2 and 4. We have recently shown that biglycan signaling through TLR 2/4 and the CD14 co-receptor regulates inflammation, suggesting that TLR co-receptors may determine whether biglycan-TLR signaling is pro- or anti-inflammatory. Here, we sought to identify other co-receptors and characterize their impact on biglycan-TLR signaling.

Clonal Expansion of Endothelial Cells Contributes to Ischemia-Induced Neovascularization.

Rationale: Vascularization is critical to maintain organ function. Although many molecular pathways were shown to control vessel growth, the genuine process of capillary formation under different conditions is unclear.

Objective: Here, we elucidated whether clonal expansion contributes to vessel growth by using Confetti mice for genetic tracing of clonally expanding endothelial cells (ECs).

Shear stress-regulated miR-27b controls pericyte recruitment by repressing SEMA6A and SEMA6D.

Aims: Vessel maturation involves the recruitment of mural cells such as pericytes and smooth muscle cells. Laminar shear stress is a major trigger for vessel maturation, but the molecular mechanisms by which shear stress affects recruitment of pericytes are unclear. MicroRNAs (miRs) are small non-coding RNAs, which post-transcriptionally control gene expression.

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A.

Endothelial cells (ECs) not only are important for oxygen delivery but also act as a paracrine source for signals that determine the balance between tissue regeneration and fibrosis. Here we show that genetic inactivation of flow-induced transcription factor Krüppel-like factor 2 (KLF2) in ECs results in reduced liver damage and augmentation of hepatocyte proliferation after chronic liver injury by treatment with carbon tetrachloride (CCl). Serum levels of GLDH3 and ALT were significantly reduced in CCl-treated EC-specific KLF2-deficient mice.

Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation.

Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells.

Rab7a and Rab27b control secretion of endothelial microRNA through extracellular vesicles.

By transporting regulatory RNAs like microRNAs, extracellular vesicles provide a novel layer of intercellular gene regulation. However, the underlying secretory pathways and the mechanisms of cargo selection are poorly understood. Rab GTPases are central coordinators of membrane trafficking with distinct members of this family being responsible for specific transport pathways.

Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3.

Objective: Cellular metabolism was recently shown to regulate endothelial cell phenotype profoundly. Whether the atheroprotective biomechanical stimulus elicited by laminar shear stress modulates endothelial cell metabolism is not known.

Approach And Results: Here, we show that laminar flow exposure reduced glucose uptake and mitochondrial content in endothelium.

Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth.

Rationale: The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long noncoding RNAs in the vasculature are largely unknown.

Objective: Here, we characterized the expression of long noncoding RNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1).

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis.

β1-Integrins are essential for angiogenesis. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor for the small Arf-GTPases Arf5 and Arf6.

Jmjd3 controls mesodermal and cardiovascular differentiation of embryonic stem cells.

Rationale: The developmental role of the H3K27 demethylases Jmjd3, especially its epigenetic regulation at target genes in response to upstream developmental signaling, is unclear.

Objective: To determine the role of Jmjd3 during mesoderm and cardiovascular lineage commitment.

Methods And Results: Ablation of Jmjd3 in mouse embryonic stem cells does not affect the maintenance of pluripotency and self-renewal but compromised mesoderm and subsequent endothelial and cardiac differentiation.

The polarity protein Scrib is essential for directed endothelial cell migration.

Rationale: Polarity proteins are involved in the apico-basal orientation of epithelial cells, but relatively little is known regarding their function in mesenchymal cells.

Objective: We hypothesized that polarity proteins also contribute to endothelial processes like angiogenesis.

Methods And Results: Screening of endothelial cells revealed high expression of the polarity protein Scribble (Scrib).

Histone deacetylase 9 promotes angiogenesis by targeting the antiangiogenic microRNA-17-92 cluster in endothelial cells.

Objective: Histone deacetylases (HDACs) modulate gene expression by deacetylation of histone and nonhistone proteins. Several HDACs control angiogenesis, but the role of HDAC9 is unclear.

Methods And Results: Here, we analyzed the function of HDAC9 in angiogenesis and its involvement in regulating microRNAs.

Heparin disrupts the CXCR4/SDF-1 axis and impairs the functional capacity of bone marrow-derived mononuclear cells used for cardiovascular repair.

Rationale: Cell therapy is a promising option for the treatment of acute or chronic myocardial ischemia. The intracoronary infusion of cells imposes the potential risk of cell clotting, which may be prevented by the addition of anticoagulants. However, a comprehensive analysis of the effects of anticoagulants on the function of the cells is missing.

Micro-RNA-34a contributes to the impaired function of bone marrow-derived mononuclear cells from patients with cardiovascular disease.

Objectives: This study evaluated the regulation and function of micro-RNAs (miRs) in bone marrow-mononuclear cells (BMCs).

Background: Although cell therapy with BMCs may represent a therapeutic option to treat patients with heart disease, the impaired functionality of patient-derived cells remains a major challenge. Small noncoding miRs post-transcriptionally control gene expression patterns and play crucial roles in modulating cell survival and function.

Phosphatidylinositol-4-phosphate 5-kinase and GEP100/Brag2 protein mediate antiangiogenic signaling by semaphorin 3E-plexin-D1 through Arf6 protein.

The semaphorins are a family of secreted or membrane-bound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells.