Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration

The damage of the skeletal muscle prompts a complex and coordinated response that involves the interactions of many different cell populations and promotes inflammation, vascular remodeling and finally muscle regeneration. Muscle disorders exist in which the irreversible loss of tissue integrity and function is linked to defective neo-angiogenesis with persistence of tissue necrosis and inflammation. Here we show that macrophages (MPs) are necessary for efficient vascular remodeling in the injured muscle. In particular, MPs sustain the differentiation of endothelial-derived progenitors to contribute to neo-capillary formation, by secreting pro-angiogenic growth factors. When phagocyte infiltration is compromised endothelial-derived progenitors undergo a significant endothelial to mesenchymal transition (EndoMT), possibly triggered by the activation of transforming growth factor-β/bone morphogenetic protein signaling, collagen accumulates and the muscle is replaced by fibrotic tissue. Our findings provide new insights in EndoMT in the adult skeletal muscle, and suggest that endothelial cells in the skeletal muscle may represent a new target for therapeutic intervention in fibrotic diseases.     

Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition

Endothelial-mesenchymal transition (EndoMT) is associated with damage to blood-brain barrier (BBB) integrity. Circular RNAs (circRNAs) are highly expressed in the brain and are involved in brain diseases; however, whether circRNAs regulate the EndoMT in the brain remains unknown. Our study demonstrated that circHECW2 regulated the EndoMT by directly binding to MIR30D, a significantly downregulated miRNA from miRNA profiling, which subsequently caused an increased expression of ATG5. These findings shed new light on the understanding of the noncanonical role of ATG5 in the EndoMT induced by methamphetamine (Meth) or lipopolysaccharide (LPS). The in vivo relevance was confirmed as microinjection of circHecw2 siRNA lentivirus into the mouse hippocampus suppressed the EndoMT induced by LPS. These findings provide novel insights regarding the contribution of circHECW2 to the nonautophagic role of ATG5 in the EndoMT process in the context of drug abuse and the broad range of neuroinflammatory disorders.     

益气温阳活血化痰方对低氧高二氧化碳性肺动脉高压的作用及其机制

目的：探讨益气温阳活血化痰方（YWHHF）经BMP-7/Smads通路抑制内皮-间质转分化（EndoMT）,从而缓解低氧高二氧化碳性大鼠肺动脉压力的机制。方法：雄性健康清洁级SD大鼠50只,体重（180~220） g,随机分为5组（n=10）：常氧组（N）、低氧高二氧化碳组（HH）、YWHHF高剂量组（YH）、中剂量组（YM）、低剂量组（YL）。N组在常氧环境下饲养,其余四组在低氧高二氧化碳（9%~11% O₂、5%~6% CO₂）环境下饲养4周,8 h/日,每周6 d。YH、YM、YL组大鼠灌胃不同浓度的益气温阳活血化痰方（3 ml/kg）,浓度分别为0.6、0.3和0.15 g/kg,HH组灌胃等体积生理盐水。4周后检测大鼠肺动脉平均压,肺灌流后取右心室游离壁及左心室加心室间隔测定右心室肥大指数。电镜观察肺超微结构变化,免疫荧光观察肺动脉结构变化,RT-PCR检测α-SMA、CD31、BMP-7、Smad1/5/8的mRNA水平,Western blot检测α-SMA、CD31、BMP-7、p-Smad1/5/8和Smad1/5/8的蛋白质水平。结果：与N组比,其余四组平均肺动脉压、右心室肥大指数均增大,镜下观察见肺有明显损伤,α-SMA mRNA及蛋白质表达升高,CD31、BMP-7、Smad1/5/8的mRNA水平降低,CD31、BMP-7、p-Smad1/5/8的蛋白质水平亦降低（P< 0.05）;与HH组比,中药组以上变化均有所减轻（P<0.05）。结论：YWHHF通过抑制EndoMT从而缓解肺动脉高压,其机制可能与促进BMP-7/Smads通路的表达有关。     

Potential role for insulin-like growth factor II and vitronectin in the endothelial-mesenchymal transition process

Endothelial-to-mesenchymal transition (EndoMT) is a process through which certain subsets of endothelial cells lose endothelial characteristics and transform into mesenchymal or smooth muscle-like cells. Emerging evidence suggests that this process plays an important role during vascular development and in many vascular pathologies. As in epithelial-mesenchymal transition, EndoMT seems to progress through a series of important steps whose interdependence and order are not clear, and that some of them are regulated by soluble growth factors. Insulin-like growth factor II (IGFII), apart from being considered important in cancer, angiogenesis, and atherosclerotic lesions, is also considered as essential to embryonic development. Here, we report that addition of IGFII promoted the EndoMT process in the presence of very low amounts of chicken serum to arrested primary embryonic aortic chicken endothelial cells attached to fibronectin (FN), gelatin, or native type I collagen. This was demonstrated by cell spreading, loss of cell-cell contacts, detachment, migration, and transformation. These cellular events also occurred when IGFII was added to medium containing vitronectin (VN). Additionally, we demonstrated that these proteins were present in the spontaneous intimal thickenings that are observed at day 11-13 of chicken embryo development. We also show that alterations in the distribution of VE-cadherin and beta-catenin occur after IGFII and serum or VN stimulation, and propose that the via VN IGFII effects may be facilitated by interaction of the mannose-6-phosphate/IGFII receptor (M6P/IGFIIR) with the urokinase-type plasminogen activator receptor (uPAR) and its ligand (uPA). Collectively, these findings provide the first evidence for a potential role of the IGFII-VN complex during the EndoMT process. From our observations and previous studies, we postulate a working hypothesis supporting a fundamental role for these molecules during EndoMT.     

Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation

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