Apelin is a bioactive peptide with diverse physiological actions on many tissues mediated by its interaction with its specific receptor APJ. Since the identification of apelin and APJ in 1998, ...pleiotropic roles of the apelin/APJ system have been elucidated in different tissues and organs, including modulation of the cardiovascular system, fluid homeostasis, metabolic pathway and vascular formation. In blood vessels, apelin and APJ expression are spatiotemporally regulated in endothelial cells (ECs) during angiogenesis. In vitro analysis revealed that the apelin/APJ system regulates angiogenesis by the induction of proliferation, migration and cord formation of cultured ECs. Moreover, apelin seems to stabilize cell-cell junctions of ECs. In addition, genetically engineered mouse models suggest that apelin/APJ regulates vascular stabilization and maturation in physiological and pathological angiogenesis. In this review, we summarize the current understanding of the apelin/APJ system for vascular formation and maturation.
Angiogenesis is controlled positively or negatively by extrinsic and intrinsic molecular cues in endothelial cells (ECs); in the tumor microenvironment, the action of positive regulators exceeds that ...of negative regulators. Thus, overinduction of negative regulators may inhibit tumor angiogenesis. MicroRNAs (miRNAs or miRs) are endogenous short noncoding RNAs regulating gene expression either through translational inhibition or destabilization of target mRNA. Here, we show that miR-125b expression is transiently induced in ECs on stimulation with vascular endothelial growth factor or by ischemia. miR-125b inhibits translation of vascular endothelial (VE)-cadherin mRNA and in vitro tube formation by ECs. Injection of miR-125b into the tumor inhibited VE-cadherin expression by ECs and induced nonfunctional blood vessel formation, resulting in inhibition of tumor growth. It has been suggested that pro-angiogenic signals in ECs also upregulate anti-angiogenic molecules simultaneously via negative feedback. Because miR-125b induction in ECs is transient after pro-angiogenic stimulation, prolonged overexpression of miR-125b could result in blood vessel regression. Thus, miR-125b may be useful in cancer therapy by causing the collapse of the lumen of ECs.
Blood vessels change their caliber to adapt to the demands of tissues or organs for oxygen and nutrients. This event is mainly organized at the capillary level and requires a size‐sensing mechanism. ...However, the molecular regulatory mechanism involved in caliber size modification in blood vessels is not clear. Here we show that apelin, a protein secreted from endothelial cells under the activation of Tie2 receptor tyrosine kinase on endothelial cells, plays a role in the regulation of caliber size of blood vessel through its cognate receptor APJ, which is expressed on endothelial cells. During early embryogenesis, APJ is expressed on endothelial cells of the new blood vessels sprouted from the dorsal aorta, but not on pre‐existing endothelial cells of the dorsal aorta. Apelin‐deficient mice showed narrow blood vessels in intersomitic vessels during embryogenesis. Apelin enhanced endothelial cell proliferation in the presence of vascular endothelial growth factor and promoted cell‐to‐cell aggregation. These results indicated that the apelin/APJ system is involved in the regulation of blood vessel diameter during angiogenesis.
Immature and unstable tumor vasculature provides an aberrant tumor microenvironment and leads to resistance of tumors to conventional therapy. Hence, normalization of tumor vessels has been reported ...to improve the effect of immuno-, chemo- and radiation therapy. However, the humoral factors, which can effectively induce maturation of tumor vasculature, have not been elucidated. In this study, we found that the novel peptide apelin and its receptor APJ can induce the morphological and functional maturation of blood vessels in tumors. This apelin-induced tumor vascular maturation enhances the efficacy of cancer dendritic cell-based immunotherapy and significantly suppresses tumor growth by promoting the infiltration of invariant natural killer T cells into the central region of the tumor and thereby robustly inducing apoptosis of tumor cells. Additionally, we showed APJ expression to be enhanced in the tumor endothelium in comparison with normal-state endothelial cells. These findings provide a new target for tumor vascular-specific maturation, which is expected to improve the efficacy of conventional cancer therapies.
Haematopoiesis and blood vessel formation are closely associated, with several molecules employed by both systems. Recently, vasohibin-1 (VASH1), an endothelium-derived negative feedback regulator of ...angiogenesis, has been isolated and characterized. VASH1 is induced by VEGF or bFGF in endothelial cells (ECs) and inhibits their proliferation and migration. However, there are no data on the induction and expression of VASH1 in haematopoietic cells (HCs). Here, we show that the haematopoietic stem cell (HSC) population, but not haematopoietic progenitors (HPs) or mature HCs from adult bone marrow (BM) constitutively express VASH1. However, HPs, but not HSCs, can be induced to express VASH1 after BM suppression by 5-FU. Knock-down of the VASH1 gene in VASH1+ leukaemia cells induced cell proliferation. These results suggest a role for VASH1 in negative feedback regulation of HP proliferation during recovery following BM ablation.
Stem cell (SC) proliferation and differentiation organize tissue homeostasis. However, how SCs regulate coordinate tissue scaling in dynamic organs remain unknown. Here, we delineate SC regulations ...in dynamic skin. We found that interfollicular epidermal SCs (IFESCs) shape basal epidermal proliferating clusters (EPCs) in expanding abdominal epidermis of pregnant mice and proliferating plantar epidermis. EPCs consist of IFESC-derived Tbx3
-basal cells (Tbx3
-BCs) and their neighboring cells where Adam8-extracellular signal-regulated kinase signaling is activated. Clonal lineage tracing revealed that Tbx3
-BC clones emerge in the abdominal epidermis during pregnancy, followed by differentiation after parturition. In the plantar epidermis, Tbx3
-BCs are sustained as long-lived SCs to maintain EPCs invariably. We showed that Tbx3
-BCs are vasculature-dependent IFESCs and identified mechanical stretch as an external cue for the vasculature-driven EPC formation. Our results uncover vasculature-mediated IFESC regulations, which explain how the epidermis adjusts its size in orchestration with dermal constituents in dynamic skin.
Permeability of blood vessels is essential for tissue homeostasis. However, disorganized hyperpermeability leads to progression of diseases. Vascular endothelial growth factor-A (VEGF) is a key ...regulator for leakiness of blood vessels and it has been reported that VEGF-mediated hyperpermeability was suppressed by angiopoietin-1 (Ang1). We found that Angiotensin-converting enzyme (ACE) was downregulated in endothelial cells by Ang1. ACE converts angiotensin I to angiotensin II (AII). Here, we studied the relationship between VEGF and AII relative to vascular permeability.
We showed that VEGF-mediated vascular hyperpermeability was suppressed in mice given AII type 1 receptor (AT1R) blocker (ARB); the effect was also seen in AT1R-deficient mice. In this system, we found that ARB inhibited VEGF-induced gap formation. Furthermore, we ascertained that angioedema induced by overexpression of VEGF decreased noticeably in ARB-treated ischemic mice.
Because ARB suppressed VEGF-induced vascular hyperpermeability, we propose that ARB may be used to minimize the risk of edema in therapeutic angiogenesis using VEGF.
Umbilical cord blood (CB) is a promising source for regeneration therapy in humans. Recently, it was shown that CB was a source of mesenchymal stem cells as well as hematopoietic stem cells, and ...further that the mesenchymal stem cells could differentiate into a number of cells types of mesenchymal lineage, such as cardiomyocytes (CMs), osteocytes, chondrocytes, and fat cells. Previously, we reported that brown adipose tissue derived cells (BATDCs) differentiated into CMs and these CMs could adapt functionally to repair regions of myocardial infarction. In this study, we examined whether CB mononuclear cells (CBMNCs) could effectively differentiate into CMs by coculturing them with BATDCs and determined which population among CBMNCs differentiated into CMs. The results show that BATDCs effectively induced CBMNCs that were non-hematopoietic stem cells (HSCs) (educated CB cells: e-CBCs) into CMs in vitro. E-CBCs reconstituted infarcted myocardium more effectively than non-educated CBMNCs or CD34-positive HSCs. Moreover, we found that e-CBCs after 3 days coculturing with BATDCs induced the most effective regeneration for impaired CMs. This suggests that e-CBCs have a high potential to differentiate into CMs and that adequate timing of transplantation supports a high efficiency for CM regeneration. This strategy might be a promising therapy for human cardiac disease.
Fas ligand (FasL) has been well characterized as a death factor. However, recent studies revealed that ectopic expression of FasL induces inflammation associated with massive neutrophil infiltration. ...We previously demonstrated that the neutrophil infiltration-inducing activity of FasL is partly dependent on, but partly independent of, IL-1β. Here we investigated the cytokine profile of peritoneal lavage fluid obtained from mice that received i.p. injections of FFL, a FasL-expressing tumor cell line. We found that FFL injection caused a marked increase of not only IL-1β but also IL-6, IL-17, IL-18, KC/chemokine CXC ligand 1 and macrophage inflammatory protein (MIP)-2, but not of IL-1α, IFN-γ, TGF-β or TNF-α. The FFL-induced cytokine production was not observed in Fas-deficient lpr mice. Among cells transfected to express individually IL-1β, IL-6, IL-17, or IL-18, only those expressing IL-1β and IL-17 induced neutrophil infiltration. In these analyses, as little as 20 pg of peritoneal IL-17 induced neutrophil infiltration. The peritoneal IL-17 levels after FFL-injection were greatly diminished in IL-1-deficient mice. However, the IL-17 level was still above the threshold for neutrophil infiltration. Consistent with this, co-administration of the anti-IL-17 antibody with FFL diminished the peritoneal KC levels and neutrophil infiltration in IL-1-deficient mice. In addition, the expression of IL-17 by the tumor cells inhibited tumor growth in wild-type and nude mice. These results indicate that FasL is an upstream inflammatory factor that induces a variety of other inflammatory cytokines in vivo, and suggest that IL-17 is involved in FasL-induced inflammation in the absence of IL-1β.
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