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The endothelium is capable of remarkable plasticity. In the embryo, primitive endothelial cells differentiate to acquire arterial, venous or lymphatic fates. Certain endothelial cells also undergo hematopoietic transition giving rise to multi-lineage hematopoietic stem and progenitors while others acquire mesenchymal properties necessary for heart development. In the adult, maintenance of differentiated endothelial state is an active process requiring constant signalling input. The failure to do so leads to the development of endothelial-to-mesenchymal transition that plays an important role in pathogenesis of a number of diseases. A better understanding of these phenotypic changes may lead to development of new therapeutic interventions. Vascular endothelium possesses remarkable plasticity in response to cues from its surroundings, leading to great heterogeneity of endothelial cells in different vascular beds. Here the authors explain the molecular basis of endothelial plasticity during embryogenesis and in various diseases.

\"She lived in a savage world in an uncivilized age - a world ruled by men and governed by the sword. The[y] called her... Red Sonja - for her flame red hair, and for the smoldering fire of her pride, which gave her sword-arm a strength that few men could match, and none had ever defeated. This collection contains a variety of issues from the original Marvel Comics series 'The Savage Sword of Conan,' as well as Sonja Tales from 'Kull and the Barbarians,' with each page re-mastered for this volume. Also included is a gallery of pin-ups by Frank Thorne, Howard Chaykin, and more. These tales are where it all began, and set the stage for the current Red Sonja series from Dynamite Entertainment\"--back cover.

Systemic and pulmonary circulations constitute a complex organ that serves multiple important biological functions. Consequently, any pathological processing affecting the vasculature can have profound systemic ramifications. Endothelial and smooth muscle are the two principal cell types composing blood vessels. Critically, endothelial proliferation and migration are central to the formation and expansion of the vasculature both during embryonic development and in adult tissues. Endothelial populations are quite heterogeneous and are both vasculature type- and organ-specific. There are profound molecular, functional, and phenotypic differences between arterial, venular and capillary endothelial cells and endothelial cells in different organs. Given this endothelial cell population diversity, it has been challenging to determine the origin of endothelial cells responsible for the angiogenic expansion of the vasculature. Recent technical advances, such as precise cell fate mapping, time-lapse imaging, genome editing, and single-cell RNA sequencing, have shed new light on the role of venous endothelial cells in angiogenesis under both normal and pathological conditions. Emerging data indicate that venous endothelial cells are unique in their ability to serve as the primary source of endothelial cellular mass during both developmental and pathological angiogenesis. Here, we review recent studies that have improved our understanding of angiogenesis and suggest an updated model of this process. Blood vessel formation: Migratory cells lining veins key to growth Cells that line the inside of veins possess a unique ability to grow new blood vessels and a better understanding of these cells could lead to new treatments for cancer, autoimmunity and other diseases associated with abnormal blood vessel formation. Michael Simons and colleagues from Yale University School of Medicine in New Haven, USA, review the attributes of venous endothelial cells, such as their unique ability to proliferate and migrate against blood flow, and then to form new intricate networks of minute blood vessels, in response to appropriate signals. The authors discuss emerging evidence implicating these cells in a variety of diseases, and suggest that drugs aimed at modulating the molecular function or migratory activities of venous endothelial cells could be used to correct abnormal blood vessel expansion.

The molecular mechanisms responsible for the development and progression of atherosclerotic lesions have not been fully established. Here, we investigated the role played by endothelial-to-mesenchymal transition (EndMT) and its key regulator FGF receptor 1 (FGFR1) in atherosclerosis. In cultured human endothelial cells, both inflammatory cytokines and oscillatory shear stress reduced endothelial FGFR1 expression and activated TGF-β signaling. We further explored the link between disrupted FGF endothelial signaling and progression of atherosclerosis by introducing endothelial-specific deletion of FGF receptor substrate 2 α (Frs2a) in atherosclerotic (Apoe(-/-)) mice. When placed on a high-fat diet, these double-knockout mice developed atherosclerosis at a much earlier time point compared with that their Apoe(-/-) counterparts, eventually demonstrating an 84% increase in total plaque burden. Moreover, these animals exhibited extensive development of EndMT, deposition of fibronectin, and increased neointima formation. Additionally, we conducted a molecular and morphometric examination of left main coronary arteries from 43 patients with various levels of coronary disease to assess the clinical relevance of these findings. The extent of coronary atherosclerosis in this patient set strongly correlated with loss of endothelial FGFR1 expression, activation of endothelial TGF-β signaling, and the extent of EndMT. These data demonstrate a link between loss of protective endothelial FGFR signaling, development of EndMT, and progression of atherosclerosis.

Lymphatic vessels are thought to arise from PROX1-positive endothelial cells (ECs) in the cardinal vein in response to induction of SOX18 expression; however, the molecular event responsible for increased SOX18 expression has not been established. We generated mice with endothelial-specific, inducible expression of an RAF1 gene with a gain-of-function mutation (RAF1(S259A)) that is associated with Noonan syndrome. Expression of mutant RAF1(S259A) in ECs activated ERK and induced SOX18 and PROX1 expression, leading to increased commitment of venous ECs to the lymphatic fate. Excessive production of lymphatic ECs resulted in lymphangiectasia that was highly reminiscent of abnormal lymphatics seen in Noonan syndrome and similar \"RASopathies.\" Inhibition of ERK signaling during development abrogated the lymphatic differentiation program and rescued the lymphatic phenotypes induced by expression of RAF1(S259A). These data suggest that ERK activation plays a key role in lymphatic EC fate specification and that excessive ERK activation is the basis of lymphatic abnormalities seen in Noonan syndrome and related diseases.

Divergent angiocrine signals from liver sinusoidal endothelial cells elicit regeneration after immediate injury and provoke fibrosis after chronic insult. CXCR7/CXCR4 balance and liver repair Shahin Rafii and colleagues show that the balance between two stromal-derived factor-1 receptors, CXCR7 and CXCR4, determines whether liver injury results in a regenerative or fibrotic response in liver sinusoidal endothelial cells (LSECs). Activation of a pro-regenerative CXCR7/Id1 pathway predominates after acute injury, whereas chronic liver injury induces sustained activation of FGFR1 in LSECs, which augments expression of CXCR4, interfering with protective CXCR7 signalling and shifting the response towards fibrogenesis. These results suggest possible strategies for developing therapeutics that facilitate the promotion of liver repair without provoking fibrosis. Chemical or traumatic damage to the liver is frequently associated with aberrant healing (fibrosis) that overrides liver regeneration 1 , 2 , 3 , 4 , 5 . The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined 6 , 7 , 8 . Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration 9 , 10 , 11 , 12 , 13 , 14 , 15 . Nevertheless, it is not known how pro-regenerative angiocrine signals from liver sinusoidal endothelial cells is subverted to promote fibrosis 16 , 17 . Here, by combining an inducible endothelial-cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury, we show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The pro-fibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors, CXCR7 and CXCR4 (refs 18 , 19 , 20 , 21 ), in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor Id1, deploying pro-regenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells ( Cxcr7 iΔEC/iΔEC ) from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors 9 , 10 , 11 . By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive FGFR1 signalling in liver sinusoidal endothelial cells counterbalanced CXCR7-dependent pro-regenerative response and augmented CXCR4 expression. This predominance of CXCR4 over CXCR7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin + hepatic stellate-like cells 22 , 23 and enforcing a pro-fibrotic vascular niche. Endothelial-cell-specific ablation of either Fgfr1 ( Fgfr1 iΔEC/iΔEC ) or Cxcr4 ( Cxcr4 iΔEC/iΔEC ) in mice restored the pro-regenerative pathway and prevented FGFR1-mediated maladaptive subversion of angiocrine factors. Similarly, selective CXCR7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Thus, we demonstrate that in response to liver injury, differential recruitment of pro-regenerative CXCR7-Id1 versus pro-fibrotic FGFR1–CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis 1 , 2 , 4 .

Somatodendritic missorting of the axonal microtubule‐associated protein Tau is an early hallmark of Alzheimer's disease (AD) and other tauopathies. Tau missorting causes synaptic loss and neuronal dysfunction, but the mechanisms underlying both normal axonal sorting and pathological missorting remain unclear. The six human brain Tau isoforms show different axodendritic distribution, but the Tau domains governing intracellular sorting and essential interactors are unknown. Here, we aimed to identify domains or motifs of human Tau and cellular binding partners required for efficient axonal Tau sorting and to unravel isoform‐specific Tau interactors. Using human MAPT‐KO induced pluripotent stem cell (iPSC)‐derived glutamatergic neurons, we analyzed the sorting behavior of more than 20 truncation‐ or phosphorylation‐mutant Tau constructs and used TurboID‐based proximity labeling and proteomics to identify sorting‐ and isoform‐specific Tau interactors. We found that efficient axonal Tau sorting was independent of the N‐terminal tail, the C‐terminal repeat domains, AD‐associated phosphorylation, and the general microtubule affinity of Tau, but it requires the presence of the proline‐rich region 2 (PRR2). Our interactome data revealed peroxisomal accumulation of the Tau N‐terminal half, while axonal Tau interacted with the PP2A activator HSP110. Further, we found 0N4R‐specific interactions of Tau with regulators of presynaptic exocytosis and postsynaptic plasticity, which are partially associated with AD pathogenesis, including members of the CDC42 pathway and the RAB11 proteins, while 0N3R‐Tau bound to various cytoskeletal elements. In sum, our study i) postulates that axonal Tau sorting relies on the PRR2 domain but not on microtubule affinity and ii) unravels a potential isoform‐specific role in synaptic function and AD‐related dysfunction. Efficient axonal Tau sorting requires the PRR2 domain but does not depend on AT8 or KXGS phosphorylation, the MT affinity, the C‐terminal repeat domains, or the N‐terminal tail of Tau. Human 0N4R‐Tau shows isoform‐specific interaction with modulators of synaptic plasticity involved in spine function under both normal and AD conditions.

Blood vascular networks in vertebrates are essential to tissue survival. Establishment of a fully functional vasculature is complex and requires a number of steps including vasculogenesis and angiogenesis that are followed by differentiation into specialized vascular tissues (i.e., arteries, veins, and lymphatics) and organ-specific differentiation. However, an equally essential step in this process is the pruning of excessive blood vessels. Recent studies have shown that pruning is critical for the effective perfusion of blood into tissues. Despite its significance, vessel pruning is the least understood process in vascular differentiation and development. Two recently published PLOS Biology papers provide important new information about cellular dynamics of vascular regression.

Endothelial phospholipase Cγ (PLCγ) is essential for vascular development; however, its role in healthy, mature, or pathological vessels is unexplored. Here, we show that PLCγ was prominently expressed in vessels of several human cancer forms, notably in renal cell carcinoma (RCC). High PLCγ expression in clear cell RCC correlated with angiogenic activity and poor prognosis, while low expression correlated with immune cell activation. PLCγ was induced downstream of vascular endothelial growth factor receptor 2 (VEGFR2) phosphosite Y1173 (pY1173). Heterozygous Vegfr2Y1173F/+ mice or mice lacking endothelial PLCγ (Plcg1iECKO) exhibited a stabilized endothelial barrier and diminished vascular leakage. Barrier stabilization was accompanied by decreased expression of immunosuppressive cytokines, reduced infiltration of B cells, helper T cells and regulatory T cells, and improved response to chemo- and immunotherapy. Mechanistically, pY1173/PLCγ signaling induced Ca2+/protein kinase C-dependent activation of endothelial nitric oxide synthase (eNOS), required for tyrosine nitration and activation of Src. Src-induced phosphorylation of VE-cadherin at Y685 was accompanied by disintegration of endothelial junctions. This pY1173/PLCγ/eNOS/Src pathway was detected in both healthy and tumor vessels in Vegfr2Y1173F/+ mice, which displayed decreased activation of PLCγ and eNOS and suppressed vascular leakage. Thus, we believe that we have identified a clinically relevant endothelial PLCγ pathway downstream of VEGFR2 pY1173, which destabilizes the endothelial barrier and results in loss of antitumor immunity.