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A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31 hi Emcn hi ), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31 hi Emcn hi vessels decrease during ageing. Here we show that expression of the miR-497∼195 cluster is high in CD31 hi Emcn hi endothelium but gradually decreases during ageing. Mice with depletion of miR-497∼195 in endothelial cells show fewer CD31 hi Emcn hi vessels and lower bone mass. Conversely, transgenic overexpression of miR-497∼195 in murine endothelium alleviates age-related reduction of type CD31 hi Emcn hi vessels and bone loss. miR-497∼195 cluster maintains the endothelial Notch activity and HIF-1α stability via targeting F-box and WD-40 domain protein (Fbxw7) and Prolyl 4-hydroxylase possessing a transmembrane domain (P4HTM) respectively. Notably, endothelialium-specific activation of miR-195 by intravenous injection of aptamer-agomiR-195 stimulates CD31 hi Emcn hi vessel and bone formation in aged mice. Together, our study indicates that miR-497∼195 regulates angiogenesis coupled with osteogenesis and may represent a potential therapeutic target for age-related osteoporosis. H-type endothelium, defined by the high expression of CD31 and endomucin, is found in the bone where it promotes angiogenesis and osteogensis. Here Yang et al . show that the miR-497∼195 cluster regulates the generation and maintenance of the H-type endothelium by controlling the levels of Notch regulator Fbxw7 and the HIF regulator P4HTM.

PECAM-1 (also known as CD31) is a cellular adhesion and signaling receptor comprising six extracellular immunoglobulin (Ig)-like homology domains, a short transmembrane domain and a 118 amino acid cytoplasmic domain that becomes serine and tyrosine phosphorylated upon cellular activation. PECAM-1 expression is restricted to blood and vascular cells. In circulating platelets and leukocytes, PECAM-1 functions largely as an inhibitory receptor that, via regulated sequential phosphorylation of its cytoplasmic domain, limits cellular activation responses. PECAM-1 is also highly expressed at endothelial cell intercellular junctions, where it functions as a mechanosensor, as a regulator of leukocyte trafficking and in the maintenance of endothelial cell junctional integrity. In this review, we will describe (1) the functional domains of PECAM-1 and how they contribute to its barrier-enhancing properties, (2) how the physical properties of PECAM-1 influence its subcellular localization and its ability to influence endothelial cell barrier function, (3) various stimuli that initiate PECAM-1 signaling and/or function at the endothelial junction and (4) cross-talk of PECAM-1 with other junctional molecules, which can influence endothelial cell function.

ObjectiveSystemic sclerosis (SSc) features multiorgan fibrosis orchestrated predominantly by activated myofibroblasts. Endothelial-to-mesenchymal transition (EndoMT) is a transdifferentiation by which endothelial cells (ECs) lose their specific morphology/markers and acquire myofibroblast-like features. Here, we determined the possible contribution of EndoMT to the pathogenesis of dermal fibrosis in SSc and two mouse models.MethodsSkin sections were immunostained for endothelial CD31 or vascular endothelial (VE)-cadherin in combination with α-smooth muscle actin (α-SMA) myofibroblast marker. Dermal microvascular ECs (dMVECs) were prepared from SSc and healthy skin (SSc-dMVECs and H-dMVECs). H-dMVECs were treated with transforming growth factor-β1 (TGFβ1) or SSc and healthy sera. Endothelial/mesenchymal markers were assessed by real-time PCR, immunoblotting and immunofluorescence. Cell contractile phenotype was assayed by collagen gel contraction.ResultsCells in intermediate stages of EndoMT were identified in dermal vessels of either patients with SSc or bleomycin-induced and urokinase-type plasminogen activator receptor (uPAR)-deficient mouse models. At variance with H-dMVECs, SSc-dMVECs exhibited a spindle-shaped appearance, co-expression of lower levels of CD31 and VE-cadherin with myofibroblast markers (α-SMA+ stress fibres, S100A4 and type I collagen), constitutive nuclear localisation of the EndoMT driver Snail1 and an ability to effectively contract collagen gels. Treatment of H-dMVECs either with SSc sera or TGFβ1 resulted in the acquisition of a myofibroblast-like morphology and contractile phenotype and downregulation of endothelial markers in parallel with the induction of mesenchymal markers. Matrix metalloproteinase-12-dependent uPAR cleavage was implicated in the induction of EndoMT by SSc sera.ConclusionsIn SSc, EndoMT may be a crucial event linking endothelial dysfunction and development of dermal fibrosis.

In the mammalian skeletal system, osteogenesis and angiogenesis are intimately linked during bone growth and regeneration in bone modeling and during bone homeostasis in bone remodeling. Recent studies have expanded our knowledge about the molecular and cellular mechanisms responsible for coupling angiogenesis and bone formation. Type H vessels, termed such because of high expression of Endomucin (Emcn) and CD31, have recently been identified and have the ability to induce bone formation. Factors including platelet-derived growth factor type BB (PDGF-BB), slit guidance ligand 3 (SLIT3), hypoxia-inducible factor 1-alpha (HIF-1α), Notch, and vascular endothelial growth factor (VEGF) are involved in the coupling of angiogenesis and osteogenesis. This review summarizes the current understanding of signaling pathways that regulate type H vessels and how type H vessels modulate osteogenesis. Further studies dissecting the regulation and function of type H vessels will provide new insights into the role of bone vasculature in the metabolism of the skeleton. We also discuss considerations for therapeutic approaches targeting type H vessels to promote fracture healing, prevent pathological bone loss, osteonecrosis, osteoarthritis, and bone metastases.

Vascular growth and remodeling are dependent on the generation of new endothelial cells from stem cells and the involvement of perivascular cells to maintain vessel integrity and function. The existence and cellular identity of vascular endothelial stem cells （VESCs） remain unclear. The perivascular pericytes in adult tissues are thought to arise from the recruitment and differentiation of mesenchymal progenitors during early development. In this study, we identified Protein C receptor-expressing （Procr＋） endothelial cells as VESCs in multiple tissues. Procr^＋ VESCs exhibit robust clonogenicity in culture, high vessel reconstitution efficiency in transplantation, long-term clonal expansion in lineage tracing, and EndMT characteristics. Moreover, Procr^＋ VESCs are bipotent, giving rise to de novo formation of endothelial cells and pericytes. This represents a novel origin of pericytes in adult angiogenesis, reshaping our understanding of blood vessel development and homeostatic process. Our study may also provide a more precise therapeutic target to inhibit pathological angiogenesis and tumor growth.

No alternative tissue-engineered vascular grafts for the abdominal venous system are reported. The present study focused on the development of new tissue-engineered vascular graft using a silk-based scaffold material for abdominal venous system replacement. A rat vein, the inferior vena cava, was replaced by a silk fibroin (SF, a biocompatible natural insoluble protein present in silk thread), tissue-engineered vascular graft (10 mm long, 3 mm diameter, n = 19, SF group). The 1 and 4 -week patency rates and histologic reactions were compared with those of expanded polytetrafluoroethylene vascular grafts (n = 10, ePTFE group). The patency rate at 1 and 4 weeks after replacement in the SF group was 100.0% and 94.7%, and that in the ePTFE group was 100.0% and 80.0%, respectively. There was no significant difference between groups ( p  = 0.36). Unlike the ePTFE graft, CD31-positive endothelial cells covered the whole luminal surface of the SF vascular graft at 4 weeks, indicating better endothelialization. SF vascular grafts may be a promising tissue-engineered scaffold material for abdominal venous system replacement.

Preostoclasts secrete PDGF-BB to promote angiogenesis in the bone, promoting bone homeostasis and preventing bone loss in an osteoporosis model. Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31 hi Emcn hi ), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31 hi Emcn hi vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase–positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31 hi Emcn hi vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31 hi Emcn hi vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31 hi Emcn hi vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.

Notch signalling in endothelial cells of the bone induces change in the capillaries and mesenchymal stem cells of the environment to support haematopoietic stem cell amplification. Age-linked changes in bone marrow Blood vessels in the bone marrow provide signals to the haematopoietic stem cells, however, how these signals modulate haematopoietic stem cell (HSC) function and change as an organism age is unclear. Ralf Adams and colleagues used imaging and cell-type-specific genetic mouse models to investigate the nature of vascular niches for HSCs in bone. They find that Notch signalling in bone endothelial cells induces change in the capillaries and mesenchymal stem cells of the environment to support HSC amplification. These signals are reduced in aged organisms, but activation of Notch can restore some of these properties. Elsewhere in this issue ( page 323 ), Tomer Itkin et al . show that the different functions of bone marrow endothelial cells are regulated by distinct types of endothelial blood vessels with different permeability properties, affecting levels of reactive oxygen species in their neighbouring stem cells. Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells 1 , 2 , 3 , 4 , 5 , 6 . The properties of niche-forming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-β (PDGFRβ)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFRβ-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.

Chronic refractory wounds are a multifactorial comorbidity of diabetes mellitus with the characteristic of impaired vascular networks. Currently, there is a lack of effective treatments for such wounds. Various types of mesenchymal stem cell-derived exosomes (MSC-exos) have been shown to exert multiple therapeutic effects on skin regeneration. We aimed to determine whether a constructed combination of human umbilical cord MSC (hUCMSC)-derived exosomes (hUCMSC-exos) and Pluronic F-127 (PF-127) hydrogel could improve wound healing. We topically applied human umbilical cord-derived MSC (hUCMSC)-derived exosomes (hUCMSC-exos) encapsulated in a thermosensitive PF-127 hydrogel to a full-thickness cutaneous wound in a streptozotocin-induced diabetic rat model. The material properties and wound healing ability of the hydrogel and cellular responses were analyzed. Compared with hUCMSC-exos, PF-127-only or control treatment, the combination of PF-127 and hUCMSC-exos resulted in a significantly accelerated wound closure rate, increased expression of CD31 and Ki67, enhanced regeneration of granulation tissue and upregulated expression of vascular endothelial growth factor (VEGF) and factor transforming growth factor beta-1 (TGFβ-1). The efficient delivery of hUCMSC-exos in PF-127 gel and improved exosome ability could promote diabetic wound healing. Thus, this biomaterial-based exosome therapy may represent a new therapeutic approach for cutaneous regeneration of chronic wounds.

Vascular injury is a common complication of type 2 diabetes mellitus (T2DM). Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a vascular regulator. This study is to explore the possible pathological mechanism of PECAM-1 in vascular injury in T2DM. Plasma PECAM-1 was detected using ELISA in plasma samples of T2DMs and normal subjects. NetworkAnalyst was used to analyze the PECAM-1 transcript genes. PECAM-1 transcriptional gene variation in T2DM was analyzed from GSE26168 data from the GEO database. STRING line network database was used to obtain the proteins related to PECAM-1, and the ClusterProfiler package in R language was applied to perform PPI, GO and KEGG enrichment analysis. PECAM-1targeted drugs prediction was performed by Drugbank. Compared with 66 healthy controls, the plasma PECAM-1 levels in 66 patients with T2DM were significantly decreased ( p  < 0.001). Moreover, multivariate regression analysis indicated that PECAM-1 was an independent risk factor for vascular injury in T2DM patients. GSE26168 data of T2DM blood mRNA showed that the levels of the PECAM-1 gene transcription factors CREB3, GATAD1 and TEAD3 were significantly reduced, while CUX1 and RELA were significantly increased in T2DM patients. Functional enrichment analysis of PPI, GO and KEGG suggested that PECAM-1 was involved in regulation of vascular stability, endothelial function, and angiogenesis. DrugBank search revealed that fostamatinib is a targeted drug closely matching the PECAM-1 molecule. In patients with T2DM, the decrease in PECAM-1 is an independent risk factor for vascular injury. Abnormalities in PECAM-1 transcriptional factors are likely associated with the reduction in plasma PECAM-1 levels, which may be involved in the mechanism of vascular injury in T2DM. Fostamatinib may be a candidate drug for vascular injury in T2DMs.