Pericytes adhere to the abluminal surface of endothelial tubules and are required for the formation of stable vascular networks. Defective endothelial cell-pericyte interactions are frequently ...observed in diseases characterized by compromised vascular integrity such as diabetic retinopathy. Many functional properties of pericytes and their exact role in the regulation of angiogenic blood vessel growth remain elusive. Here we show that pericytes promote endothelial sprouting in the postnatal retinal vasculature. Using genetic and pharmacological approaches, we show that the expression of vascular endothelial growth factor receptor 1 (VEGFR1) by pericytes spatially restricts VEGF signalling. Angiogenic defects caused by pericyte depletion are phenocopied by intraocular injection of VEGF-A or pericyte-specific inactivation of the murine gene encoding VEGFR1. Our findings establish that pericytes promote endothelial sprouting, which results in the loss of side branches and the enlargement of vessels when pericyte function is impaired or lost.
Activities as diverse as migration, proliferation and patterning occur simultaneously and in a coordinated fashion during tissue morphogenesis. In the growing vasculature, the formation of motile, ...invasive and filopodia-carrying endothelial sprouts is balanced with the stabilization of blood-transporting vessels. Here, we show that sprouting endothelial cells in the retina have high rates of VEGF uptake, VEGF receptor endocytosis and turnover. These internalization processes are opposed by atypical protein kinase C activity in more stable and mature vessels. aPKC phosphorylates Dab2, a clathrin-associated sorting protein that, together with the transmembrane protein ephrin-B2 and the cell polarity regulator PAR-3, enables VEGF receptor endocytosis and downstream signal transduction. Accordingly, VEGF receptor internalization and the angiogenic growth of vascular beds are defective in loss-of-function mice lacking key components of this regulatory pathway. Our work uncovers how vessel growth is dynamically controlled by local VEGF receptor endocytosis and the activity of cell polarity proteins.
BACKGROUNDTo mitigate the COVID-19 pandemic, many countries have recommended the use of booster vaccinations. The relationship between the degree of adverse vaccine reactions and elevated antibody ...titers is of interest; however, no studies have investigated the temporal changes in antibody titers based on repeated measurements after a third dose of the BNT162b2 vaccine. METHODSThis prospective longitudinal cohort study was conducted with 62 healthcare workers who received a third dose of the BNT162b2 at Okayama University Hospital, Japan. Venous blood draw and fingertip whole blood test sample collection were conducted at the early (3-13 days) and 1-month time points; only FWT sample collection was conducted at the 2-month time point. Information on adverse reactions within 1 week after vaccination was also obtained. The association between fever of 37.5 °C or higher and antibody titers after the third dose of BNT162b2 was examined using a mixed-effects model and Poisson regression with robust variance. RESULTSA trend toward higher antibody titers in the early period after vaccination was observed in the febrile individuals, but the differences were not significant at 1 and 2 months post-vaccination (the partial regression coefficient for fever was 8094.3 -1910.2, 18,098.8 at 1 month after vaccination, and 1764.1 -4133.9, 7662.1 at 2 months after vaccination in the adjusted models). CONCLUSIONThe findings suggest that the presence of fever after the third vaccine does not predict a sustained elevation in serum antibody titers.
During development, regeneration and in certain pathological settings, the vasculature is expanded and remodeled substantially. Proper morphogenesis and function of blood vessels are essential in ...multicellular organisms. Upon stimulation with growth factors including vascular endothelial growth factors (VEGFs), the activation, internalization and sorting of receptor tyrosine kinases (RTKs) orchestrate developmental processes and the homeostatic maintenance of all organs including the vasculature. Previously, RTK signaling was thought to occur exclusively at the plasma membrane, a process that was subsequently terminated by endocytosis and receptor degradation. However, this model turned out to be an oversimplification and there is now a substantial amount of reports indicating that receptor internalization and trafficking to intracellular compartments depends on coreceptors leading to the activation of specific signaling pathways. Here we review the latest findings concerning endocytosis and intracellular trafficking of VEGFRs. The body of evidence is compelling that VEGF receptor trafficking is coordinated with other proteins such as Neuropilin-1, ephrin-B2, VE-cadherin and protein phosphatases.
► This review summarizes the influence of Coreceptors on VEGFR2 trafficking. ► Influence of NRP1 on VEGFR2 trafficking. ► Influence of Ephrin-B2 on VEGFR2 trafficking. ► Influence of VE-cadherin on VEGFR2 trafficking and signaling.
In development, tissue regeneration or certain diseases, angiogenic growth leads to the expansion of blood vessels and the lymphatic vasculature. This involves endothelial cell proliferation as well ...as angiogenic sprouting, in which a subset of cells, termed tip cells, acquires motile, invasive behaviour and extends filopodial protrusions. Although it is already appreciated that angiogenesis is triggered by tissue-derived signals, such as vascular endothelial growth factor (VEGF) family growth factors, the resulting signalling processes in endothelial cells are only partly understood. Here we show with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium. We link this pro-angiogenic function to a crucial role of ephrin-B2 in the VEGF signalling pathway, which we have studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1, Akt and the mitogen-activated protein kinase Erk. Our results show that full VEGFR3 signalling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth.
The peripheral nervous system has astonishing regenerative capabilities in that cut nerves are able to reconnect and re-establish their function. Schwann cells are important players in this process, ...during which they dedifferentiate to a progenitor/stem cell and promote axonal regrowth. Here, we report that fibroblasts also play a key role. Upon nerve cut, ephrin-B/EphB2 signaling between fibroblasts and Schwann cells results in cell sorting, followed by directional collective cell migration of Schwann cells out of the nerve stumps to guide regrowing axons across the wound. Mechanistically, we find that cell-sorting downstream of EphB2 is mediated by the stemness factor Sox2 through N-cadherin relocalization to Schwann cell-cell contacts. In vivo, loss of EphB2 signaling impaired organized migration of Schwann cells, resulting in misdirected axonal regrowth. Our results identify a link between Ephs and Sox proteins, providing a mechanism by which progenitor cells can translate environmental cues to orchestrate the formation of new tissue.
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► Fibroblasts sort Schwann cells into cords at nerve wounds via ephrin-B signaling ► The Schwann cell cords then guide axonal regrowth across the wound site ► Sox2 promotes relocalization of N-cadherin to Schwann cell junctions ► EphB2 loss in vivo disrupts directed Schwann cell migration and axon regrowth
The expression of immune checkpoint proteins such as programmed cell death protein 1 (PD‐1) and its ligand (PD‐L1) has been shown to correlate with patient prognosis in many malignant cancers. The ...expression of PD‐L1 is controlled by c‐Myc; however, further upstream regulation of PD‐L1 expression is largely unknown. We have previously shown that atypical protein kinase C lambda/iota (aPKCλ) phosphorylates the Forkhead box protein O1 (FoxO1) transcription factor at Ser218 to suppress its DNA‐binding ability, thereby regulating c‐Myc expression and controlling physiologic and pathologic endothelial proliferation. The presence of phosphorylation of FoxO1 at Ser218 (pSer218 FoxO1) in cutaneous angiosarcoma (CAS) strongly correlates with poor patient prognosis. Here, we reported that patients with PD‐L1+ cells in CAS lesions showed significantly worse prognosis compared to those that were PD‐L1−. Expression of PD‐L1 correlated with that of aPKCλ or the presence of pSer218FoxO1. Moreover, suppression of aPKCλ expression or inhibition of its activity in HUVECs or AS‐M, an established human angiosarcoma cell line, resulted in decreased PD‐L1 expression. Our results suggest that combined treatment with immune checkpoint inhibitors and aPKCλ inhibitors could be a novel treatment strategy for CAS patients.
Programmed cell death ligand 1 (PD‐L1) expression associated with the expression level of atypical protein kinase C (aPKC) and phosphorylation of Forkhead box protein O1 (FoxO1) at Ser218 by aPKC. It was shown that aPKC controls PD‐L1 expression through FoxO1 phosphorylation.
Weathering, referring to techniques for depicting outdoor objects as having suffered rain and wind damage, has a long history of research, and many methods can be found in the literature. Metal is a ...representative target of weathering, as metallic surface corrosion is a widespread deterioration phenomenon in our daily life. However, few weathering methods consider the effects of rust-preventive paint, while real metal is usually treated with a preservative. This paper presents a novel procedural method for weathering coated metal objects. In our method, a coated surface is imposed on a 3D triangular mesh. We enable the mechanical deterioration of coating film, and we deform the mesh model to express cracking and peeling. As further defacing elements on the coating film, runoff rust and darkening are reproduced by changing the color and reflectance of the surface. Besides, by locally adjusting the control parameters of the designated areas on the surface, the process of deterioration can be arbitrarily directed. Several visual simulation results are shown to prove empirically the faithfulness of the proposed methods.
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