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Eph-ephrin signaling couples endothelial cell sorting and arterial specification
Arteries are vital blood vessels for our body and their growth and patterning are critical for proper blood flow. Here they use a retina model to show that a balance of EphB4 receptor and ephrin-B2 ligand integrate a well-wired molecular network to control arteriovenous patterning and vascular growth.
- Jonas Stewen
- , Kai Kruse
- & Mara E. Pitulescu
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Osteocyte mitochondria regulate angiogenesis of transcortical vessels
Osteocytes are the key cellular components of cortical bone. Here they show that osteocytes transfer mitochondria to the endothelial cells of transcortical vessels (TCVs), which promotes angiogenesis and increases function of the TCV network.
- Peng Liao
- , Long Chen
- & Junjie Gao
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Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts
During alveologenesis myofibroblasts contractions at terminal sacs produce alveoli in the lungs. Here they show that endothelial cells promote myofibroblast-driven alveologenesis by forming basement membranes via Rap1-induced integrin β1 activation.
- Haruko Watanabe-Takano
- , Katsuhiro Kato
- & Shigetomo Fukuhara
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Hydrogels with tunable mechanical plasticity regulate endothelial cell outgrowth in vasculogenesis and angiogenesis
It is vital to unveil the effects of extracellular matrix cues on endothelial cell (EC) outgrowth for desirably governing vasculature formation, but the role of matrix plasticity on EC outgrowth is elusive. Here, the authors develop hydrogels with tunable mechanical plasticity independent of stiffness, and elucidate the plasticity-mediated responses of ECs during vasculogenesis and angiogenesis.
- Zhao Wei
- , Meng Lei
- & Feng Xu
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Protective effects of macrophage-specific integrin α5 in myocardial infarction are associated with accentuated angiogenesis
During myocardial infarction, cardiac macrophages expand, become activated and play an important role in cardiac repair and remodelling. Here the authors show that integrin α5 is upregulated in infarct macrophages and contributes to myocardial repair, triggering an angiogenic phenotype and protecting from adverse remodelling.
- Ruoshui Li
- , Bijun Chen
- & Nikolaos G. Frangogiannis
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hapln1a+ cells guide coronary growth during heart morphogenesis and regeneration
The guidance cues critical for coronary growth remain unclear. Here, Sun et al. reveal the requirement of hapln1a+ cells and serpine1 to establish a microenvironment for guided coronary growth during zebrafish heart morphogenesis and regeneration.
- Jisheng Sun
- , Elizabeth A. Peterson
- & Jinhu Wang
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Epigenetic landscape reveals MECOM as an endothelial lineage regulator
Errors in vascular development are associated with several congenital defects. Here they systematically investigated the epigenetic landscape of the endothelial lineage and found that MECOM depletion impairs endothelial cell differentiation and angiogenesis.
- Jie Lv
- , Shu Meng
- & Lili Zhang
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Extracellular vesicles engineering by silicates-activated endothelial progenitor cells for myocardial infarction treatment in male mice
Extracellular vesicle therapy has shown great potential for the treatment of myocardial infarction. Here, the authors show a silicate biomaterials-based approach to engineer extracellular vesicles from endothelial progenitor cells with high yield and bioactivity for treating myocardial infarction.
- Bin Yu
- , Hekai Li
- & Caiwen Ou
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Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2
The authors report that endothelial protocadherin FAT1 inhibits endothelial proliferation and angiogenesis by promoting degradation of the transcriptional cofactors YAP and TAZ by direct interaction with the E3 ubiquitin ligase Mind Bomb-2 (MIB2).
- Rui Li
- , Jingchen Shao
- & Stefan Offermanns
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Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice
ACE inhibitors are widely used to treat cardiovascular diseases and promote angiogenesis. Here, the authors show a central role for endothelial USP7-Sp1/Sp3-Notch1 signalling in pathophysiological angiogenesis in response to ACE inhibitor treatment.
- Hanlin Lu
- , Peidong Yuan
- & Wencheng Zhang
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Large-scale perfused tissues via synthetic 3D soft microfluidics
Bioengineering live tissues has remained challenging due to limited nutrient exchange in the growing tissues. Here, the authors have developed micro-perfused 2-photon printing of 3D microfluidics, to engineer large-scale, viable and functional neural and hepatic 3D tissues.
- Sergei Grebenyuk
- , Abdel Rahman Abdel Fattah
- & Adrian Ranga
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In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis
The lineage relationship between blood and endothelial cells has been difficult to examine due to the multiphasic timing of hematopoiesis in the embryo. Here the authors use using in vivo barcoding technology to assess cell ancestry and show that blood and endothelial cells emerge through common (haemangioblast) or separate (mesenchymoangioblasts and haematomesoblasts) progenitors in the yolk sac.
- C. Biben
- , T. S. Weber
- & S. Taoudi
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GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression
Gpr174 is a regulator of regulatory T cells, which play an important role in angiogenesis after hindlimb ischemia. Here, the authors show GPR174-deficient Tregs promote AREG expression by inhibiting Gαs/cAMP/PKA signal pathway and increasing EGR1 nuclear accumulation to improve angiogenesis and vascular remodeling in response to ischemic injury.
- Jin Liu
- , Lihong Pan
- & Aijun Sun
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An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression
Vascular addressins control lymphocyte homing, thus regulating immunity and inflammation, but how addressin expression is patterned remains unknown. Here the authors identify composite DNA elements (NCCEs) that bind NKX2 homeodomain proteins cooperatively with COUP-TFII to define a morphogenetic code that targets transcription of mucosal vascular addressins.
- Thanh Theresa Dinh
- , Menglan Xiang
- & Eugene C. Butcher
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Integration of single-cell transcriptomes and biological function reveals distinct behavioral patterns in bone marrow endothelium
Here Kim et al. show that primary BMECs can be maintained ex vivo as distinct sinusoidal- and arterial-like populations and that the presence of macrophages is critical to preserve their native transcriptomic profiles and functional heterogeneity.
- Young-Woong Kim
- , Greta Zara
- & Nadia Carlesso
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Endothelial cell cycle state determines propensity for arterial-venous fate
During blood vessel development, endothelial cells become specified toward arterial or venous fates. Chavkin et al find that distinct endothelial cell cycle states provide windows of opportunity for the molecular induction of arterial or venous fate.
- Nicholas W. Chavkin
- , Gael Genet
- & Karen K. Hirschi
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Rab35 governs apicobasal polarity through regulation of actin dynamics during sprouting angiogenesis
The promiscuous GTPase Rab35 has been shown to be involved in many important cellular functions. In this article, Francis et al. illustrate how Rab35 acts as a critical brake to actin remodeling during sprouting angiogenesis and how it is necessary for proper blood vessel development.
- Caitlin R. Francis
- , Hayle Kincross
- & Erich J. Kushner
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Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability
Functional vascular tree formation is a key step in many contexts, such as cancer, and Neuropilin1 (NRP1) has been associated with adhesion receptor endocytic turnover. Here, authors show NRP1 and its mini-WARS ligand play a role in reducing endothelial permeability.
- Noemi Gioelli
- , Lisa J. Neilson
- & Guido Serini
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ADAMTS18+ villus tip telocytes maintain a polarized VEGFA signaling domain and fenestrations in nutrient-absorbing intestinal blood vessels
The molecular mechanisms ensuring the specialized structure of small intestinal villus tip blood vessels are incompletely understood. Here the authors show that ADAMTS18+ telocytes maintain a “just-right” level and location of VEGFA signaling on intestinal villus blood vessels, thereby ensuring the presence of endothelial fenestrae for nutrient absorption, while avoiding excessive leakiness and destabilization of villus tip epithelial structures.
- Jeremiah Bernier-Latmani
- , Cristina Mauri
- & Tatiana V. Petrova
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Endothelial cell heterogeneity and microglia regulons revealed by a pig cell landscape at single-cell level
Pigs are important large animal models for biomedical research. Here, the authors construct a single-cell landscape of pig tissues, unravelling the phenotypic heterogeneity of blood endothelial cells in adipose tissues and the evolutionally conserved regulons of microglia in brains.
- Fei Wang
- , Peiwen Ding
- & Yonglun Luo
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Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth
The study shows that mechanical forces trigger secretion of the extracellular matrix protein dentin matrix protein 1 from osteoblasts. This transforms bone growth-promoting blood vessels into a quiescent subtype to limit bone growth at the end of adolescence.
- Maria Dzamukova
- , Tobias M. Brunner
- & Max Löhning
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Mechanical loading of intraluminal pressure mediates wound angiogenesis by regulating the TOCA family of F-BAR proteins
Chemical and mechanical cues coordinately regulate angiogenesis. Here, the authors show that blood flow-driven intraluminal pressure regulates wound angiogenesis. Findings indicate that TOCA family of F-BAR proteins act as actin regulators required for endothelial cell migration and sense mechanical cell stretching to regulate wound angiogenesis.
- Shinya Yuge
- , Koichi Nishiyama
- & Shigetomo Fukuhara
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Transmembrane stem cell factor protein therapeutics enhance revascularization in ischemia without mast cell activation
Stem cell factor (SCF) is a cytokine with great potential for treating ischemia, stroke and heart attack, but therapies using SCF have been limited by acute allergic responses. The work describes a new therapeutic using transmembrane SCF delivered in lipid nanocarriers that is effective in treating ischemia without off-target effects.
- Eri Takematsu
- , Miles Massidda
- & Aaron B. Baker
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Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling
The molecular mechanisms through which pulmonary endothelial progenitor cells stimulate lung angiogenesis are not clear. Here, authors show that these cells stimulate the growth of alveolar capillaries and alveoli of newborn mice through FOXF1 and FLI1 nuclear protein-activation of the BMP9/ACVRL1/SMAD1 signaling pathway.
- Guolun Wang
- , Bingqiang Wen
- & Vladimir V. Kalinichenko
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A specialized bone marrow microenvironment for fetal haematopoiesis
The colonization of bone marrow by haematopoietic stem and progenitor cells is critical for lifelong blood cell formation. Here the authors report distinct features of fetal bone marrow and show that artery-derived signals promote haematopoietic colonization.
- Yang Liu
- , Qi Chen
- & Ralf H. Adams
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βIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling
Defective angiogenesis remains a high source of morbidity in multiple disorders. Here they show that βIV-spectrin, a membrane-associated cytoskeletal protein, is essential for regulation of endothelial tip cell populations and VEGF signaling during sprouting angiogenesis.
- Eun-A Kwak
- , Christopher C. Pan
- & Nam Y. Lee
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Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies
Primary congenital glaucoma (PCG) is characterised by increased intraocular pressure, and variants in ANGPT1, or SVEP1 have been identified as risk alleles. Here, the authors show that deletion of these genes induces glaucoma in mice, and that activation of ANGPT1-TEK signaling ameliorates disease progression in mouse models.
- Benjamin R. Thomson
- , Pan Liu
- & Susan E. Quaggin
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A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis
UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.
- Davide Pradella
- , Gianluca Deflorian
- & Claudia Ghigna
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Coordination of endothelial cell positioning and fate specification by the epicardium
It remains unclear how spatial information controls endothelial cell identity and behavior in the developing heart. Here the authors perform single cell RNA sequencing at key developmental timepoints in mice to interrogate cellular contributions to coronary vessel patterning and maturation in the epicardium.
- Pearl Quijada
- , Michael A. Trembley
- & Eric M. Small
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The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets
As more intersection points between platelets and the immune system are found, the role of platelets for vessel growth in the adult organism remains unclear. The authors demonstrate that platelets negatively modulate revascularization through CXCL4 secretion induced by activation C5aR1 on their surface.
- Henry Nording
- , Lasse Baron
- & Harald F. Langer
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Synthetic extracellular matrices with tailored adhesiveness and degradability support lumen formation during angiogenic sprouting
Current tissue engineering strategies lack materials that promote angiogenesis. Here the authors develop a microfluidic in vitro model in which chemokine-guided endothelial cell sprouting into a tunable hydrogel is followed by the formation of perfusable lumens to determine the material properties that regulate angiogenesis.
- Jifeng Liu
- , Hongyan Long
- & Britta Trappmann
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Article
| Open Access
FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis
Mitochondria-associated ER membranes (MAMs) are involved in the regulation of many cellular functions. Here, the authors report that FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes play an essential role in the process of angiogenesis and neoangiogenesis.
- Cheng Wang
- , Xiaoyan Dai
- & Kai Huang
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A junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis
Communication between endothelial leader and follower cells during collective cell migration is crucial for vascular development. Here, the authors show that PACSIN2 guides collective cell migration and angiogenesis by recruiting a protein trafficking complex to asymmetric cell-cell junctions, controlling local junction plasticity.
- Tsveta S. Malinova
- , Ana Angulo-Urarte
- & Stephan Huveneers
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| Open Access
Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis
Glucocorticoids (GCs) inhibit bone angiogenesis and affect bone development, but the underlying mechanisms remain unclear. Here, the authors show that GCs induce vascular cell senescence during bone development by inhibiting angiogenin secretion from osteoclasts, impairing angiogenesis via endothelial Plexin B2, resulting in unpaired bone growth.
- Xiaonan Liu
- , Yu Chai
- & Mei Wan
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| Open Access
Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner
ZEB2 transcription factor is increased in a subset of cardiomyocytes during stress to induce cardioprotective effects after injury. Here the authors show that therapeutic delivery of ZEB2 prevents cardiac dysfunction after ischemic damage and promotes the activation of pro-angiogenic signals.
- Monika M. Gladka
- , Arwa Kohela
- & Eva van Rooij
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| Open Access
Blood and lymphatic systems are segregated by the FLCN tumor suppressor
Blood and lymphatic vessels bear a strong resemblance but do not share a lumen, thus maintaining their distinct functions. Here, the authors describe that Folliculin, a tumor suppressor, prevents the fusion of these vessels during development by limiting the plasticity of venous and lymphatic endothelial cells.
- Ikue Tai-Nagara
- , Yukiko Hasumi
- & Yoshiaki Kubota
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Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size
During lumen formation in blood vessels, endothelial cells become exposed to hemodynamic forces that induce membrane blebbing and changes in cell shape. Here, the authors show endothelial cells develop an actin-based protective mechanism in the cell cortex that prevents excessive blebbing to control cell shape and vessel diameter.
- Igor Kondrychyn
- , Douglas J. Kelly
- & Li-Kun Phng
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| Open Access
Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis
Slug supports heart development and tumor metastasis, but its role in blood vessel formation is less clear. Here the authors show that endothelial cell-expressed Slug regulates both physiologic and pathological angiogenesis, at least in part through the modulation of Notch signalling.
- Nan W. Hultgren
- , Jennifer S. Fang
- & Christopher C. W. Hughes
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| Open Access
The GEF Trio controls endothelial cell size and arterial remodeling downstream of Vegf signaling in both zebrafish and cell models
Arterial flow regulates artery diameter but other mechanisms may also affect this. Here, the authors show that the guanine nucleotide exchange factor Trio and GTPases Rac1 and RhoG, triggers F-actin remodeling in arterial endothelial cells, independent of flow, to enhance lumen diameter in zebrafish and cell models.
- Alina Klems
- , Jos van Rijssel
- & Ferdinand le Noble
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| Open Access
Distinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi
Intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. Here the authors show that VEGF-C expression in specialized IntSCs is regulated by YAP/TAZ, and VEGF-C is responsible for maintaining lacteal integrity, thus influencing dietary fat drainage into lacteals.
- Seon Pyo Hong
- , Myung Jin Yang
- & Gou Young Koh
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Article
| Open Access
VEGFR2 signaling drives meningeal vascular regeneration upon head injury
Severe head injury results in critical damage of blood vessels of the meninges and brain parenchyma. Here, the authors describe key pathways governing meningeal vascular regeneration following head injury, characterizing the differential roles of VEGFR2, Tie2, Dll4 and PDGFRβ signaling.
- Bong Ihn Koh
- , Hyuek Jong Lee
- & Injune Kim
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Article
| Open Access
A molecular map of murine lymph node blood vascular endothelium at single cell resolution
The origin and diversity of blood vascular endothelial cells (BEC) in lymphoid tissues is unclear. Here, the authors profile murine BECs from peripheral lymph nodes by single cell analysis and identify subsets of cells specialised for immune cell recruitment and vascular homeostasis.
- Kevin Brulois
- , Anusha Rajaraman
- & Eugene C. Butcher
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| Open Access
The Bartonella autotransporter BafA activates the host VEGF pathway to drive angiogenesis
Pathogenic bacteria of the genus Bartonella can induce vasoproliferative lesions during infection. Here, Tsukamoto et al. show that this effect is caused by a secreted protein that induces cell proliferation and angiogenesis by acting as an analog of the host’s vascular endothelial growth factor (VEGF).
- Kentaro Tsukamoto
- , Naoaki Shinzawa
- & Yohei Doi
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| Open Access
Single-cell transcriptomic analysis identifies the conversion of zebrafish Etv2-deficient vascular progenitors into skeletal muscle
The signals restricting specification of vascular progenitors are unclear. Here, the authors use scRNAseq to identify transitional steps during blood and vascular development in zebrafish and identify Etv2 as repressing skeletal muscle differentiation in vascular progenitors.
- Brendan Chestnut
- , Satish Casie Chetty
- & Saulius Sumanas
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| Open Access
Specific fibroblast subpopulations and neuronal structures provide local sources of Vegfc-processing components during zebrafish lymphangiogenesis
How and where VEGF-C is processed in lymphangiogenesis is unclear. Here, the authors show that development of the zebrafish lymphatic system is locally restricted by Vegfc maturation causing lymphatic sprouting in certain regions, which is regulated by the metalloproteases ADAMTS3 and ADAMTS14.
- Guangxia Wang
- , Lars Muhl
- & Andreas van Impel
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| Open Access
Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways
In the central nervous system, the maturation of glial cells is temporally and functionally coupled with that of the vascular network during postnatal development. Here the authors show that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling, while astroglial HIFα participates through Wnt-dependent signaling.
- Sheng Zhang
- , Bokyung Kim
- & Fuzheng Guo
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| Open Access
Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
Tumors can overproduce pro-angiogenic ligands overcoming currently approved anti-angiogenic therapies and hindering their success. Here, the authors show that targeting phosphoinositide recycling during tumor angiogenesis harnesses the tumor’s own production of angiogenic ligands to deplete adjacent endothelial cells of the capacity to respond to these signals.
- Amber N. Stratman
- , Olivia M. Farrelly
- & Brant M. Weinstein
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| Open Access
Molecular determinants of nephron vascular specialization in the kidney
The kidney is vascularized with highly specialized and zonated endothelial cells that are essential for its filtration function. Here, Barry et al. provide a single-cell RNA sequencing analysis of the kidney vasculature that highlights its transcriptional heterogeneity and uncovers pathways important for its development and function.
- David M. Barry
- , Elizabeth A. McMillan
- & Shahin Rafii
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| Open Access
Integrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy
Integrin-linked kinase (ILK) is an important mediator of integrin signaling. Here Park et al. show that mice with endothelial-specific deletion of Ilk develop vascular defects that resemble familial exudative vitreoretinopathy, and identify mutations in ILK in patients with exudative vitreoretinopathy suggesting a potential role in human pathogenesis.
- Hongryeol Park
- , Hiroyuki Yamamoto
- & Ralf H. Adams
Parenchymal cues define Vegfa-driven venous angiogenesis by activating a sprouting competent venous endothelial subtype