Publications by authors named "Anne Eichmann"

110 Publications

Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling.

Proc Natl Acad Sci U S A 2021 Sep;118(37)

Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT 06511;

Endothelial cell (EC) sensing of wall fluid shear stress (FSS) from blood flow governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels. Low FSS triggers inward remodeling to restore normal FSS but the regulatory mechanisms are unknown. In this paper, we describe the signaling network that governs inward artery remodeling. FSS induces Smad2/3 phosphorylation through the type I transforming growth factor (TGF)-β family receptor Alk5 and the transmembrane protein Neuropilin-1, which together increase sensitivity to circulating bone morphogenetic protein (BMP)-9. Smad2/3 nuclear translocation and target gene expression but not phosphorylation are maximal at low FSS and suppressed at physiological high shear. Reducing flow by carotid ligation in rodents increases Smad2/3 nuclear localization, while the resultant inward remodeling is blocked by the EC-specific deletion of Alk5. The flow-activated MEKK3/Klf2 pathway mediates the suppression of Smad2/3 nuclear translocation at high FSS, mainly through the cyclin-dependent kinase (CDK)-2-dependent phosphosphorylation of the Smad linker region. Thus, low FSS activates Smad2/3, while higher FSS blocks nuclear translocation to induce inward artery remodeling, specifically at low FSS. These results are likely relevant to inward remodeling in atherosclerotic vessels, in which Smad2/3 is activated through TGF-β signaling.
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http://dx.doi.org/10.1073/pnas.2105339118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449390PMC
September 2021

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis.

Nat Commun 2021 08 11;12(1):4872. Epub 2021 Aug 11.

Istituto di Genetica Molecolare "Luigi Luca Cavalli-Sforza", Consiglio Nazionale delle Ricerche, Pavia, Italy.

The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B's necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis.
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http://dx.doi.org/10.1038/s41467-021-24998-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358048PMC
August 2021

Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development.

J Am Soc Nephrol 2021 Sep 2;32(9):2255-2272. Epub 2021 Aug 2.

Department of Cellular and Molecular Physiology, Yale University Medical School, New Haven, Connecticut

Background: Kidney function requires continuous blood filtration by glomerular capillaries. Disruption of glomerular vascular development or maintenance contributes to the pathogenesis of kidney diseases, but the signaling events regulating renal endothelium development remain incompletely understood. Here, we discovered a novel role of Slit2-Robo signaling in glomerular vascularization. Slit2 is a secreted polypeptide that binds to transmembrane Robo receptors and regulates axon guidance as well as ureteric bud branching and angiogenesis.

Methods: We performed Slit2-alkaline phosphatase binding to kidney cryosections from mice with or without tamoxifen-inducible or deletions, and we characterized the phenotypes using immunohistochemistry, electron microscopy, and functional intravenous dye perfusion analysis.

Results: Only the glomerular endothelium, but no other renal endothelial compartment, responded to Slit2 in the developing kidney vasculature. Induced gene deletion or Slit2 ligand trap at birth affected nephrogenesis and inhibited vascularization of developing glomeruli by reducing endothelial proliferation and migration, leading to defective cortical glomerular perfusion and abnormal podocyte differentiation. Global and endothelial-specific Robo deletion showed that both endothelial and epithelial Robo receptors contributed to glomerular vascularization.

Conclusions: Our study provides new insights into the signaling pathways involved in glomerular vascular development and identifies Slit2 as a potential tool to enhance glomerular angiogenesis.
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http://dx.doi.org/10.1681/ASN.2020111640DOI Listing
September 2021

Specialized endothelial tip cells guide neuroretina vascularization and blood-retina-barrier formation.

Dev Cell 2021 Aug 16;56(15):2237-2251.e6. Epub 2021 Jul 16.

Centre de Recherche, CHU St. Justine, Montréal, QC H3T 1C5, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC H3T 1J4, Canada. Electronic address:

Endothelial tip cells guiding tissue vascularization are primary targets for angiogenic therapies. Whether tip cells require differential signals to develop their complex branching patterns remained unknown. Here, we show that diving tip cells invading the mouse neuroretina (D-tip cells) are distinct from tip cells guiding the superficial retinal vascular plexus (S-tip cells). D-tip cells have a unique transcriptional signature, including high TGF-β signaling, and they begin to acquire blood-retina barrier properties. Endothelial deletion of TGF-β receptor I (Alk5) inhibits D-tip cell identity acquisition and deep vascular plexus formation. Loss of endothelial ALK5, but not of the canonical SMAD effectors, leads to aberrant contractile pericyte differentiation and hemorrhagic vascular malformations. Oxygen-induced retinopathy vasculature exhibits S-like tip cells, and Alk5 deletion impedes retina revascularization. Our data reveal stage-specific tip cell heterogeneity as a requirement for retinal vascular development and suggest that non-canonical-TGF-β signaling could improve retinal revascularization and neural function in ischemic retinopathy.
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http://dx.doi.org/10.1016/j.devcel.2021.06.021DOI Listing
August 2021

Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

Circulation 2021 Sep 29;144(10):805-822. Epub 2021 Jun 29.

Cardiovascular Research Center, Department of Internal Medicine (H.P., J.F., M.P., M.C., S.Y., M.A.S., A.E.), Yale University School of Medicine, New Haven, CT.

Background: Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles.

Methods: Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina.

Results: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in -deficient mice.

Conclusions: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429266PMC
September 2021

SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia.

J Clin Invest 2021 Aug;131(16)

Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.

SLIT2 is a secreted polypeptide that guides migration of cells expressing Roundabout 1 and 2 (ROBO1 and ROBO2) receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient-derived GBM xenografts reduced tumor growth and rendered tumors sensitive to immunotherapy. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1- and ROBO2-mediated PI3K-γ activation. Macrophage Robo1 and Robo2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a potentially novel regulator of the GBM microenvironment and immunotherapeutic target for brain tumors.
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http://dx.doi.org/10.1172/JCI141083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363292PMC
August 2021

Alphastatin-C a new inhibitor of endothelial cell activation is a pro-arteriogenic agent and retards B16-F10 melanoma growth in a preclinical model.

Oncotarget 2020 Dec 22;11(51):4770-4787. Epub 2020 Dec 22.

Special Laboratory of Applied Toxinology, Center of Toxins, Immune-Response and Cell Signaling (CeTICS), Butantan Institute, São Paulo, SP, Brazil.

Most characterized angiogenic modulators are proteolytic fragments of structural plasma and/or matrix components. Herein, we have identified a novel anti-angiogenic peptide generated by the hydrolysis of the C-terminal moiety of the fibrinogen alpha chain, produced by the snake venom metalloprotease bothropasin (SVMP), a hemorrhagic proteinase in Bothrops jararaca venom. The 14-amino acids peptide (alphastatin-C) is a potent antagonist of basic fibroblast growth factor, induced endothelial cell (HUVEC-CS) proliferation, migration and capillary tube formation in matrigel. It also inhibits cell adhesion to fibronectin. The basis of the antagonism between bFGF and alphastatin-C is elucidated by the inhibition of various bFGF induced signaling pathways and their molecular components modification, whenever the combination of the stimuli is provided, in comparison to the treatment with bFGF only. To corroborate to the potential therapeutic use of alphastatin-C, we have chosen to perform assays in two distinct angiogenic settings. In chick model, alphastatin-C inhibits chorioallantoic membrane angiogenesis. In mouse, it efficiently reduces tumor number and volume in a melanoma model, due to the impairment of tumor neovascularization in treated mice. In contrast, we show that the alphastatin-C peptide induces arteriogenesis, increasing pial collateral density in neonate mice. alphastatin-C is an efficient new antiangiogenic FGF-associated agent , it is an inhibitor of embryonic and tumor vascularization while, it is an arteriogenic agent. The results also suggest that SVMPs can be used as biochemical tools to process plasma and/or matrix macromolecular components unraveling new angiostatic peptides.
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http://dx.doi.org/10.18632/oncotarget.27839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771711PMC
December 2020

Endothelial S1P Signaling Counteracts Infarct Expansion in Ischemic Stroke.

Circ Res 2021 02 2;128(3):363-382. Epub 2020 Dec 2.

Vascular Biology Program, Boston Children's Hospital, MA (T.H.).

Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P modulation in stroke.

Objective: To address roles and mechanisms of engagement of endothelial cell S1P in the naive and ischemic brain and its potential as a target for cerebrovascular therapy.

Methods And Results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P in the mouse brain. With an S1P signaling reporter, we reveal that abluminal polarization shields S1P from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P-selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion.

Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P agonists.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874503PMC
February 2021

BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells.

J Biol Chem 2020 12 23;295(52):18179-18188. Epub 2020 Oct 23.

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9-mediated internalization of ALK-1, BMP-9-dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9-induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9-mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.
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http://dx.doi.org/10.1074/jbc.RA120.015680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939458PMC
December 2020

SLIT3 deficiency attenuates pressure overload-induced cardiac fibrosis and remodeling.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Section of Pediatric Cardiovascular Surgery, Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

In pulmonary hypertension and certain forms of congenital heart disease, ventricular pressure overload manifests at birth and is an obligate hemodynamic abnormality that stimulates myocardial fibrosis, which leads to ventricular dysfunction and poor clinical outcomes. Thus, an attractive strategy is to attenuate the myocardial fibrosis to help preserve ventricular function. Here, by analyzing RNA-sequencing databases and comparing the transcript and protein levels of fibrillar collagen in WT and global-knockout mice, we found that slit guidance ligand 3 (SLIT3) was present predominantly in fibrillar collagen-producing cells and that SLIT3 deficiency attenuated collagen production in the heart and other nonneuronal tissues. We then performed transverse aortic constriction or pulmonary artery banding to induce left and right ventricular pressure overload, respectively, in WT and knockout mice. We discovered that SLIT3 deficiency abrogated fibrotic and hypertrophic changes and promoted long-term ventricular function and overall survival in both left and right ventricular pressure overload. Furthermore, we found that SLIT3 stimulated fibroblast activity and fibrillar collagen production, which coincided with the transcription and nuclear localization of the mechanotransducer yes-associated protein 1. These results indicate that SLIT3 is important for regulating fibroblast activity and fibrillar collagen synthesis in an autocrine manner, making it a potential therapeutic target for fibrotic diseases, especially myocardial fibrosis and adverse remodeling induced by persistent afterload elevation.
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http://dx.doi.org/10.1172/jci.insight.136852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406261PMC
June 2020

Lymphatic Endothelial Cell Junctions: Molecular Regulation in Physiology and Diseases.

Front Physiol 2020 29;11:509. Epub 2020 May 29.

Department of Cellular and Molecular Physiology, Cardiovascular Research Center, Yale School of Medicine, Yale University, New Haven, CT, United States.

Lymphatic endothelial cells (LECs) lining lymphatic vessels develop specialized cell-cell junctions that are crucial for the maintenance of vessel integrity and proper lymphatic vascular functions. Successful lymphatic drainage requires a division of labor between lymphatic capillaries that take up lymph via open "button-like" junctions, and collectors that transport lymph to veins, which have tight "zipper-like" junctions that prevent lymph leakage. In recent years, progress has been made in the understanding of these specialized junctions, as a result of the application of state-of-the-art imaging tools and novel transgenic animal models. In this review, we discuss lymphatic development and mechanisms governing junction remodeling between button and zipper-like states in LECs. Understanding lymphatic junction remodeling is important in order to unravel lymphatic drainage regulation in obesity and inflammatory diseases and may pave the way towards future novel therapeutic interventions.
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http://dx.doi.org/10.3389/fphys.2020.00509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274196PMC
May 2020

Anatomy and function of the vertebral column lymphatic network in mice.

Nat Commun 2019 10 9;10(1):4594. Epub 2019 Oct 9.

Université Pierre et Marie Curie Paris 06 UMRS1127, Sorbonne Université, Institut du Cerveau et de la Moelle Epinière, Paris, France.

Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues.
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http://dx.doi.org/10.1038/s41467-019-12568-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785564PMC
October 2019

Cardiomyocyte d-dopachrome tautomerase protects against heart failure.

JCI Insight 2019 09 5;4(17). Epub 2019 Sep 5.

Yale Cardiovascular Research Center.

The mechanisms contributing to heart failure remain incompletely understood. d-dopachrome tautomerase (DDT) is a member of the macrophage migration inhibitory factor family of cytokines and is highly expressed in cardiomyocytes. This study examined the role of cardiomyocyte DDT in the setting of heart failure. Patients with advanced heart failure undergoing transplantation demonstrated decreased cardiac DDT expression. To understand the effect of loss of cardiac DDT in experimental heart failure, cardiomyocyte-specific DDT-KO (DDT-cKO) and littermate control mice underwent surgical transverse aortic constriction (TAC) to induce cardiac pressure overload. DDT-cKO mice developed more rapid cardiac contractile dysfunction, greater cardiac dilatation, and pulmonary edema after TAC. Cardiomyocytes from DDT-cKO mice after TAC had impaired contractility, calcium transients, and reduced expression of the sarcoplasmic reticulum calcium ATPase. The DDT-cKO hearts also exhibited diminished angiogenesis with reduced capillary density and lower VEGF-A expression after TAC. In pharmacological studies, recombinant DDT (rDDT) activated endothelial cell ERK1/2 and Akt signaling and had proangiogenic effects in vitro. The DDT-cKO hearts also demonstrated more interstitial fibrosis with enhanced collagen and connective tissue growth factor expression after TAC. In cardiac fibroblasts, rDDT had an antifibrotic action by inhibiting TGF-β-induced Smad-2 activation. Thus, endogenous cardiomyocyte DDT has pleiotropic actions that are protective against heart failure.
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http://dx.doi.org/10.1172/jci.insight.128900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777911PMC
September 2019

Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis.

Nat Commun 2019 05 28;10(1):2350. Epub 2019 May 28.

Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.

Endothelial cell migration, proliferation and survival are triggered by VEGF-A activation of VEGFR2. However, how these cell behaviors are regulated individually is still unknown. Here we identify Endophilin-A2 (ENDOA2), a BAR-domain protein that orchestrates CLATHRIN-independent internalization, as a critical mediator of endothelial cell migration and sprouting angiogenesis. We show that EndoA2 knockout mice exhibit postnatal angiogenesis defects and impaired front-rear polarization of sprouting tip cells. ENDOA2 deficiency reduces VEGFR2 internalization and inhibits downstream activation of the signaling effector PAK but not ERK, thereby affecting front-rear polarity and migration but not proliferation or survival. Mechanistically, VEGFR2 is directed towards ENDOA2-mediated endocytosis by the SLIT2-ROBO pathway via SLIT-ROBO-GAP1 bridging of ENDOA2 and ROBO1. Blocking ENDOA2-mediated endothelial cell migration attenuates pathological angiogenesis in oxygen-induced retinopathy models. This work identifies a specific endocytic pathway controlling a subset of VEGFR2 mediated responses that could be targeted to prevent excessive sprouting angiogenesis in pathological conditions.
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http://dx.doi.org/10.1038/s41467-019-10359-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538628PMC
May 2019

To BBB or Not to BBB?

Dev Cell 2018 12;47(6):689-691

INSERM U970, Paris Cardiovascular Research Center, 56 Rue Leblanc, 75015 Paris, France; Cardiovascular Research Center and the Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510-3221, USA. Electronic address:

In this issue of Developmental Cell, Anbalagan et al. demonstrate that pituicytes, a subtype of astroglia, drive endothelial cell permeability in the zebrafish embryo neurohypophysis. This occurs via secretion of Vegfa/Tgfβ3 permeability factors that promote formation of fenestrae and the repression of anti-inflammatory retinoic acid signaling that induces tight cell junctions.
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http://dx.doi.org/10.1016/j.devcel.2018.11.039DOI Listing
December 2018

The Intestinal Lymphatic System: Functions and Metabolic Implications.

Cell Mol Gastroenterol Hepatol 2019 14;7(3):503-513. Epub 2018 Dec 14.

Cardiovascular Research Center and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut; INSERM U970, Paris Cardiovascular Research Center, Paris, France.

The lymphatic system of the gut plays important roles in the transport of dietary lipids, as well as in immunosurveillance and removal of interstitial fluid. Historically, despite its crucial functions in intestinal homeostasis, the lymphatic system has been poorly studied. In the last 2 decades, identification of specific molecular mediators of lymphatic endothelial cells (LECs) growth together with novel genetic approaches and intravital imaging techniques, have advanced our understanding of the mechanisms regulating intestinal lymphatic physiology in health and disease. As its metabolic implications are gaining recognition, intestinal lymphatic biology is currently experiencing a surge in interest. This review describes current knowledge related to molecular control of intestinal lymphatic vessel structure and function. We discuss regulation of chylomicron entry into lymphatic vessels by vascular endothelial growth factors (VEGFs), hormones, transcription factors and the specific signaling pathways involved. The information covered supports the emerging role of intestinal lymphatics in etiology of the metabolic syndrome and their potential as a therapeutic target.
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http://dx.doi.org/10.1016/j.jcmgh.2018.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396433PMC
June 2019

NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy.

Nat Commun 2018 08 27;9(1):3463. Epub 2018 Aug 27.

Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06511, USA.

Pericytes are mural cells that surround capillaries and control angiogenesis and capillary barrier function. During sprouting angiogenesis, endothelial cell-derived platelet-derived growth factor-B (PDGF-B) regulates pericyte proliferation and migration via the platelet-derived growth factor receptor-β (PDGFRβ). PDGF-B overexpression has been associated with proliferative retinopathy, but the underlying mechanisms remain poorly understood. Here we show that abnormal, α-SMA-expressing pericytes cover angiogenic sprouts and pathological neovascular tufts (NVTs) in a mouse model of oxygen-induced retinopathy. Genetic lineage tracing demonstrates that pericytes acquire α-SMA expression during NVT formation. Pericyte depletion through inducible endothelial-specific knockout of Pdgf-b decreases NVT formation and impairs revascularization. Inactivation of the NCK1 and NCK2 adaptor proteins inhibits pericyte migration by preventing PDGF-B-induced phosphorylation of PDGFRβ at Y1009 and PAK activation. Loss of Nck1 and Nck2 in mural cells prevents NVT formation and vascular leakage and promotes revascularization, suggesting PDGFRβ-Y1009/NCK signaling as a potential target for the treatment of retinopathies.
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http://dx.doi.org/10.1038/s41467-018-05926-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110853PMC
August 2018

Lacteal junction zippering protects against diet-induced obesity.

Science 2018 08;361(6402):599-603

Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06510-3221, USA.

Excess dietary lipid uptake causes obesity, a major global health problem. Enterocyte-absorbed lipids are packaged into chylomicrons, which enter the bloodstream through intestinal lymphatic vessels called lacteals. Here, we show that preventing lacteal chylomicron uptake by inducible endothelial genetic deletion of () and (; also known as ) renders mice resistant to diet-induced obesity. Absence of NRP1 and FLT1 receptors increased VEGF-A bioavailability and signaling through VEGFR2, inducing lacteal junction zippering and chylomicron malabsorption. Restoring permeable lacteal junctions by VEGFR2 and vascular endothelial (VE)-cadherin signaling inhibition rescued chylomicron transport in the mutant mice. Zippering of lacteal junctions by disassembly of cytoskeletal VE-cadherin anchors prevented chylomicron uptake in wild-type mice. These data suggest that lacteal junctions may be targets for preventing dietary fat uptake.
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http://dx.doi.org/10.1126/science.aap9331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317738PMC
August 2018

SMAD4 Prevents Flow Induced Arteriovenous Malformations by Inhibiting Casein Kinase 2.

Circulation 2018 11;138(21):2379-2394

Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut.

Background: Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder that causes arteriovenous malformations (AVMs). Mutations in the genes encoding Endoglin ( ENG) and activin-receptor-like kinase 1 ( AVCRL1 encoding ALK1) cause HHT type 1 and 2, respectively. Mutations in the SMAD4 gene are present in families with juvenile polyposis-HHT syndrome that involves AVMs. SMAD4 is a downstream effector of transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP) family ligands that signal via activin-like kinase receptors (ALKs). Ligand-neutralizing antibodies or inducible, endothelial-specific Alk1 deletion induce AVMs in mouse models as a result of increased PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) signaling. Here we addressed if SMAD4 was required for BMP9-ALK1 effects on PI3K/AKT pathway activation.

Methods: The authors generated tamoxifen-inducible, postnatal, endothelial-specific Smad4 mutant mice ( Smad4).

Results: We found that loss of endothelial Smad4 resulted in AVM formation and lethality. AVMs formed in regions with high blood flow in developing retinas and other tissues. Mechanistically, BMP9 signaling antagonized flow-induced AKT activation in an ALK1- and SMAD4-dependent manner. Smad4 endothelial cells in AVMs displayed increased PI3K/AKT signaling, and pharmacological PI3K inhibitors or endothelial Akt1 deletion both rescued AVM formation in Smad4 mice. BMP9-induced SMAD4 inhibited casein kinase 2 ( CK2) transcription, in turn limiting PTEN phosphorylation and AKT activation. Consequently, CK2 inhibition prevented AVM formation in Smad4 mice.

Conclusions: Our study reveals SMAD4 as an essential effector of BMP9-10/ALK1 signaling that affects AVM pathogenesis via regulation of CK2 expression and PI3K/AKT1 activation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309254PMC
November 2018

Development and plasticity of meningeal lymphatic vessels.

J Exp Med 2017 Dec 15;214(12):3645-3667. Epub 2017 Nov 15.

Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS.
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http://dx.doi.org/10.1084/jem.20170391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716035PMC
December 2017

Basic research: Where do new endothelial cells come from in the injured heart?

Nat Rev Cardiol 2017 Sep 3;14(9):507-508. Epub 2017 Aug 3.

Cardiovascular Research Center and the Department of Cellular and Molecular Physiology, 300 George Street, Yale University School of Medicine, New Haven, Connecticut 06510-3221, USA; and at INSERM U970, Paris Cardiovascular Research Center, 56 Rue Leblanc, 75015 Paris, France.

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http://dx.doi.org/10.1038/nrcardio.2017.121DOI Listing
September 2017

FGF-dependent metabolic control of vascular development.

Nature 2017 05 3;545(7653):224-228. Epub 2017 May 3.

Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, USA.

Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/Fgfr3 double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development.
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http://dx.doi.org/10.1038/nature22322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427179PMC
May 2017

Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein-Induced Retinal Angiogenesis.

Arterioscler Thromb Vasc Biol 2017 04 23;37(4):657-663. Epub 2017 Feb 23.

From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.-W.L., R.O., W.P.D., Y.Q., A.E., S.-W.J.); Department of Biology and McAllister Heart Institute, University of North Carolina, Chapel Hill (D.C.C., V.L.B.); Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.); School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Korea (J.K., S.-W.J.); and Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor (V.M.K.).

Objective: Increasing evidence suggests that bone morphogenetic protein (BMP) signaling regulates angiogenesis. Here, we aimed to define the function of BMP receptors in regulating early postnatal angiogenesis by analysis of inducible, endothelial-specific deletion of the BMP receptor components (BMP type 2 receptor), (activin receptor-like kinase 1), , and in mouse retinal vessels.

Approach And Results: Expression analysis of several BMP ligands showed that proangiogenic BMP ligands are highly expressed in postnatal retinas. Consistently, BMP receptors are also strongly expressed in retina with a distinct pattern. To assess the function of BMP signaling in retinal angiogenesis, we first generated mice carrying an endothelial-specific inducible deletion of . Postnatal deletion of in endothelial cells substantially decreased the number of angiogenic sprouts at the vascular front and branch points behind the front, leading to attenuated radial expansion. To identify critical BMPR1s (BMP type 1 receptors) associated with BMPR2 in retinal angiogenesis, we generated endothelial-specific inducible deletion of 3 BMPR1s abundantly expressed in endothelial cells and analyzed the respective phenotypes. Among these, endothelial-specific deletion of either / or / caused a delay in radial expansion, reminiscent of vascular defects associated with postnatal endothelial-specific deletion of BMPR2, suggesting that ALK2/ACVR1 and ALK3/BMPR1A are likely to be the critical BMPR1s necessary for proangiogenic BMP signaling in retinal vessels.

Conclusions: Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential proangiogenic cue for retinal vessels.
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http://dx.doi.org/10.1161/ATVBAHA.116.308422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382795PMC
April 2017

PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia.

Nat Commun 2016 11 29;7:13650. Epub 2016 Nov 29.

Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.

Activin receptor-like kinase 1 (ALK1) is an endothelial serine-threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.
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http://dx.doi.org/10.1038/ncomms13650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141347PMC
November 2016

The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization.

Nat Commun 2016 11 24;7:13517. Epub 2016 Nov 24.

Cardiovascular Research Center, Yale University School of Medicine, Department of Internal Medecine Cardiology, New Haven, Connecticut 06510-3221, USA.

Vascular permeability and neovascularization are implicated in many diseases including retinopathies and diabetic wound healing. Robo4 is an endothelial-specific transmembrane receptor that stabilizes the vasculature, as shown in Robo4 mice that develop hyperpermeability, but how Robo4 signals remained unclear. Here we show that Robo4 deletion enhances permeability and revascularization in oxygen-induced retinopathy (OIR) and accelerates cutaneous wound healing. To determine Robo4 signalling pathways, we generated transgenic mice expressing a truncated Robo4 lacking the cytoplasmic domain (Robo4ΔCD). Robo4ΔCD expression is sufficient to prevent permeability, and inhibits OIR revascularization and wound healing in Robo4 mice. Mechanistically, Robo4 does not affect Slit2 signalling, but Robo4 and Robo4ΔCD counteract Vegfr2-Y949 (Y951 in human VEGFR2) phosphorylation by signalling through the endothelial UNC5B receptor. We conclude that Robo4 inhibits angiogenesis and vessel permeability independently of its cytoplasmic domain, while activating VEGFR2-Y951 via ROBO4 inhibition might accelerate tissue revascularization in retinopathy of prematurity and in diabetic patients.
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http://dx.doi.org/10.1038/ncomms13517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123080PMC
November 2016

Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells.

Nat Commun 2016 11 21;7:13516. Epub 2016 Nov 21.

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL.
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http://dx.doi.org/10.1038/ncomms13516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121336PMC
November 2016

Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia.

J Cell Biol 2016 09 19;214(7):807-16. Epub 2016 Sep 19.

Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511 Department of Cell Biology, Yale University, New Haven, CT 06510 Department of Biomedical Engineering, Yale University, New Haven, CT 06510

Morphogenesis of the vascular system is strongly modulated by mechanical forces from blood flow. Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal-dominant disease in which arteriovenous malformations and telangiectasias accumulate with age. Most cases are linked to heterozygous mutations in Alk1 or Endoglin, receptors for bone morphogenetic proteins (BMPs) 9 and 10. Evidence suggests that a second hit results in clonal expansion of endothelial cells to form lesions with poor mural cell coverage that spontaneously rupture and bleed. We now report that fluid shear stress potentiates BMPs to activate Alk1 signaling, which correlates with enhanced association of Alk1 and endoglin. Alk1 is required for BMP9 and flow responses, whereas endoglin is only required for enhancement by flow. This pathway mediates both inhibition of endothelial proliferation and recruitment of mural cells; thus, its loss blocks flow-induced vascular stabilization. Identification of Alk1 signaling as a convergence point for flow and soluble ligands provides a molecular mechanism for development of HHT lesions.
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http://dx.doi.org/10.1083/jcb.201603106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037412PMC
September 2016

BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration.

Oncotarget 2016 Aug;7(35):55957-55969

Department of Biomedical Sciences, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.

Age-related macular degeneration (AMD) is the leading cause of blindness in aging populations of industrialized countries. The drawbacks of inhibitors of vascular endothelial growth factor (VEGFs) currently used for the treatment of AMD, which include resistance and potential serious side-effects, require the identification of new therapeutic targets to modulate angiogenesis. BMP9 signaling through the endothelial Alk1 serine-threonine kinase receptor modulates the response of endothelial cells to VEGF and promotes vessel quiescence and maturation during development. Here, we show that BMP9/Alk1 signaling inhibits neovessel formation in mouse models of pathological ocular angiogenesis relevant to AMD. Activating Alk1 signaling in laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) inhibited neovascularization and reduced the volume of vascular lesions. Alk1 signaling was also found to interfere with VEGF signaling in endothelial cells whereas BMP9 potentiated the inhibitory effects of VEGFR2 signaling blockade, both in OIR and laser-induced CNV. Together, our data show that targeting BMP9/Alk1 efficiently prevents the growth of neovessels in AMD models and introduce a new approach to improve conventional anti-VEGF therapies.
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http://dx.doi.org/10.18632/oncotarget.11182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302889PMC
August 2016

Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity.

Circ Res 2016 Aug 27;119(5):607-20. Epub 2016 Jun 27.

From the INSERM U970, Paris Center for Cardiovascular Research (PARCC), Paris, France (L.P., L.P.-F., T.M., A.E.); Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (A.D., M.S., A.E.); and INSERM U1050, Collège de France, Centre Interdisciplinaire de Recherche en Biologie (CIRB), Paris, France (I.E., I.B.).

Rationale: Arterial endothelial cells are morphologically, functionally, and molecularly distinct from those found in veins and lymphatic vessels. How arterial fate is acquired during development and maintained in adult vessels is incompletely understood.

Objective: We set out to identify factors that promote arterial endothelial cell fate in vivo.

Methods And Results: We developed a functional assay, allowing us to monitor and manipulate arterial fate in vivo, using arteries isolated from quails that are grafted into the coelom of chick embryos. Endothelial cells migrate out from the grafted artery, and their colonization of host arteries and veins is quantified. Here we show that sympathetic innervation promotes arterial endothelial cell fate in vivo. Removal of sympathetic nerves decreases arterial fate and leads to colonization of veins, whereas exposure to sympathetic nerves or norepinephrine imposes arterial fate. Mechanistically, sympathetic nerves increase endothelial ERK (extracellular signal-regulated kinase) activity via adrenergic α1 and α2 receptors.

Conclusions: These findings show that sympathetic innervation promotes arterial endothelial fate and may lead to novel approaches to improve arterialization in human disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.308473DOI Listing
August 2016

miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart.

Sci Rep 2016 Feb 18;6:21228. Epub 2016 Feb 18.

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06520, USA.

Myocardial hypertrophy is an adaptive response to hemodynamic demands. Although angiogenesis is critical to support the increase in heart mass with matching blood supply, it may also promote a hypertrophic response. Previously, we showed that cardiac angiogenesis induced by placental growth factor (PlGF), promotes myocardial hypertrophy through the paracrine action of endothelium-derived NO, which triggers the degradation of regulator of G protein signaling 4 (RGS4) to activate the Akt/mTORC1 pathways in cardiomyocytes. Here, we investigated whether miRNAs contribute to the development of hypertrophic response associated with myocardial angiogenesis. We show that miR-182 is upregulated concurrently with the development of hypertrophy in PlGF mice, but not when hypertrophy was blocked by concomitant expression of PlGF and RGS4, or by PlGF expression in eNOS(-/-) mice. Anti-miR-182 treatment inhibits the hypertrophic response and prevents the Akt/mTORC1 activation in PlGF mice and NO-treated cardiomyocytes. miR-182 reduces the expression of Bcat2, Foxo3 and Adcy6 to regulate the hypertrophic response in PlGF mice. Particularly, depletion of Bcat2, identified as a new miR-182 target, promotes Akt(Ser473)/p70-S6K(Thr389) phosphorylation and cardiomyocyte hypertrophy. LV pressure overload did not upregulate miR-182. Thus, miR-182 is a novel target of endothelial-cardiomyocyte crosstalk and plays an important role in the angiogenesis induced-hypertrophic response.
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http://dx.doi.org/10.1038/srep21228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758045PMC
February 2016
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