"Sprouting angiogenesis", a reappraisal.

Angiogenesis is defined as a new blood vessel sprouting from pre-existing vessels. This highly regulated process take place through two non-exclusive events, the so-called endothelial sprouting or non-sprouting (intussusceptive) microvascular growth. This review article will provide a brief overview of some relevant topics defining sprouting angiogenesis and including: (i) The concept of functional specialization of endothelial cells during different phases of this process, involving the specification of endothelial cells into tip cells, stalk cells, and phalanx cells bearing different morphologies and functional properties; (ii) The interplay between numerous signaling pathways, including Notch and Notch ligands, VEGF and VEGFRs, semaphorins, and netrins, in the regulation and modulation of the phenotypic characteristics of these cells; (iii) Some fundamental and consecutive morphological processes, including lumen formation and perfusion, network formation, remodeling, pruning, leading to the final vessel maturation and stabilization.

[1]  T. Skalak,et al.  The Role of Mechanical Stresses in Microvascular Remodeling , 1996, Microcirculation.

[2]  John C Chappell,et al.  Local guidance of emerging vessel sprouts requires soluble Flt-1. , 2009, Developmental cell.

[3]  J. Stone,et al.  Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity , 1995, Nature Medicine.

[4]  J. Rossant,et al.  The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. , 1995, The EMBO journal.

[5]  B Swolin,et al.  Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. , 1994, Genes & development.

[6]  G. Davis,et al.  This Review Is Part of a Thematic Series on Vascular Cell Diversity, Which Includes the following Articles: Heart Valve Development: Endothelial Cell Signaling and Differentiation Molecular Determinants of Vascular Smooth Muscle Cell Diversity Endothelial/pericyte Interactions Endothelial Extracellu , 2022 .

[7]  H. Gerhardt,et al.  Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting , 2010, Nature Cell Biology.

[8]  T. Sato,et al.  Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Antonio Duarte,et al.  Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation , 2008, Nature.

[10]  V. Bautch.  Endothelial Cells Form a Phalanx to Block Tumor Metastasis , 2009, Cell.

[11]  S. Selleck,et al.  dally, a Drosophila member of the glypican family of integral membrane proteoglycans, affects cell cycle progression and morphogenesis via a Cyclin A-mediated process. , 2002, Journal of cell science.

[12]  Elisabetta Dejana,et al.  Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. , 2004, Physiological reviews.

[13]  P. Burri,et al.  Intussusceptive arborization contributes to vascular tree formation in the chick chorio-allantoic membrane , 2000, Anatomy and Embryology.

[14]  Eliot R. Clark,et al.  Microscopic observations on the growth of blood capillaries in the living mammal , 1939 .

[15]  Holger Gerhardt,et al.  Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis , 2007, Nature.

[16]  K. Guan,et al.  Class IV Semaphorins Promote Angiogenesis by Stimulating Rho-Initiated Pathways through Plexin-B , 2004, Cancer Research.

[17]  J. Rhodin,et al.  Capillary growth in the mesentery of normal young rats. Intravital video and electron microscope analyses. , 1989, Journal of submicroscopic cytology and pathology.

[18]  W. Risau,et al.  Regression of blood vessels precedes cartilage differentiation during chick limb development. , 1987, Differentiation; research in biological diversity.

[19]  Holger Gerhardt,et al.  Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration , 2008, Nature.

[20]  Martin Friedlander,et al.  Mechanisms of endothelial cell guidance and vascular patterning in the developing mouse retina , 2006, Progress in Retinal and Eye Research.

[21]  Anirban Datta,et al.  PTEN-Mediated Apical Segregation of Phosphoinositides Controls Epithelial Morphogenesis through Cdc42 , 2007, Cell.

[22]  L. Reid,et al.  New findings in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. , 1976, British journal of experimental pathology.

[23]  J. Stone,et al.  Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  Pamela F. Jones,et al.  Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis , 1996, Cell.

[25]  H. Gerhardt,et al.  Endothelial development taking shape. , 2011, Current opinion in cell biology.

[26]  M. Krasnow,et al.  Tube Morphogenesis Making and Shaping Biological Tubes , 2003, Cell.

[27]  P. Burri,et al.  Implementation of intussusceptive microvascular growth in the chicken chorioallantoic membrane (CAM): 1. pillar formation by folding of the capillary wall. , 1996, Microvascular research.

[28]  M. Iruela-Arispe,et al.  Cellular and molecular mechanisms of vascular lumen formation. , 2009, Developmental cell.

[29]  S. Paku,et al.  First steps of tumor-related angiogenesis. , 1991, Laboratory investigation; a journal of technical methods and pathology.

[30]  Nathan D. Lawson,et al.  Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries , 2007, Nature.

[31]  Li Yuan,et al.  The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system , 2004, Nature.

[32]  Antonio Duarte,et al.  The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching , 2007, Proceedings of the National Academy of Sciences.

[33]  P. Carmeliet,et al.  Role of tissue factor in embryonic blood vessel development , 1996, Nature.

[34]  L. Reid,et al.  Changes in the pulmonary arteries of the rat during recovery from hypoxia-induced pulmonary hypertension. , 1977, British journal of experimental pathology.

[35]  Y. Ogura,et al.  Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease , 2003, Nature Medicine.

[36]  T. Doetschman,et al.  Tubedown-1 in remodeling of the developing vitreal vasculature in vivo and regulation of capillary outgrowth in vitro. , 2002, Developmental biology.

[37]  Judah Folkman,et al.  Angiogenesis in vitro , 1980, Nature.

[38]  M. N. Nakatsu,et al.  Optimized fibrin gel bead assay for the study of angiogenesis. , 2007, Journal of visualized experiments : JoVE.

[39]  Jacqueline Murray,et al.  Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis , 2011, Development.

[40]  L Orci,et al.  In vitro rapid organization of endothelial cells into capillary-like networks is promoted by collagen matrices , 1983, The Journal of cell biology.

[41]  B. Geiger,et al.  The molecular organization of endothelial cell to cell junctions: differential association of plakoglobin, beta-catenin, and alpha- catenin with vascular endothelial cadherin (VE-cadherin) , 1995, The Journal of cell biology.

[42]  A. Patz,et al.  Studies on diabetic retinopathy. 3. Influence of diabetes on intramural pericytes. , 1968, Archives of ophthalmology.

[43]  Ruijin Huang,et al.  Remodeling of aortic smooth muscle during avian embryonic development , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[44]  P. D’Amore,et al.  Vascular Development: Cellular and Molecular Regulation , 2022 .

[45]  Christopher C W Hughes,et al.  Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-beta in vascular morphogenesis. , 2008, Circulation research.

[46]  C. Cepko,et al.  Flk-1, a Receptor for Vascular Endothelial Growth Factor (VEGF), Is Expressed by Retinal Progenitor Cells , 1996, The Journal of Neuroscience.

[47]  R. Levy,et al.  Blood flow reprograms lymphatic vessels to blood vessels. , 2012, The Journal of clinical investigation.

[48]  Ali Cinar,et al.  An agent-based model for the investigation of neovascularization within porous scaffolds. , 2011, Tissue engineering. Part A.

[49]  J. Bishop,et al.  Macrophages are required for cell death and tissue remodeling in the developing mouse eye , 1993, Cell.

[50]  P. Eggli,et al.  First blood vessels in the avian neural tube are formed by a combination of dorsal angioblast immigration and ventral sprouting of endothelial cells. , 1996, Developmental biology.

[51]  A. Nadas,et al.  Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features. , 1979, The American journal of physiology.

[52]  Marcus Fruttiger,et al.  The Notch Ligands Dll4 and Jagged1 Have Opposing Effects on Angiogenesis , 2009, Cell.

[53]  P. McLoughlin,et al.  Chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulation , 2003, The Journal of physiology.

[54]  Amber N. Stratman,et al.  Endothelial Cell-Pericyte Interactions Stimulate Basement Membrane Matrix Assembly: Influence on Vascular Tube Remodeling, Maturation, and Stabilization , 2011, Microscopy and Microanalysis.

[55]  M. Klagsbrun,et al.  Neurovascular congruence results from a shared patterning mechanism that utilizes Semaphorin3A and Neuropilin-1. , 2003, Developmental biology.

[56]  R. Nicosia,et al.  Rat aortic smooth muscle cells become pericytes during angiogenesis in vitro. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[57]  W. Risau,et al.  Regression of vessels in the tunica vasculosa lentis is initiated by coordinated endothelial apoptosis: A role for vascular endothelial growth factor as a survival factor for endothelium , 1998, Developmental dynamics : an official publication of the American Association of Anatomists.

[58]  S. Bray.  Notch signalling: a simple pathway becomes complex , 2006, Nature Reviews Molecular Cell Biology.

[59]  T. Kuwabara,et al.  Regression of the tunica vasculosa lentis in the postnatal rat. , 1981, Investigative ophthalmology & visual science.

[60]  F. Orsenigo,et al.  CCM1 regulates vascular-lumen organization by inducing endothelial polarity , 2010, Journal of Cell Science.

[61]  G. Davis,et al.  RGD-Dependent Vacuolation and Lumen Formation Observed during Endothelial Cell Morphogenesis in Three-Dimensional Fibrin Matrices Involves the αvβ3 and α5β1 Integrins , 2000 .

[62]  T. Kume.  Novel insights into the differential functions of Notch ligands in vascular formation , 2009, Journal of angiogenesis research.

[63]  R. Adams,et al.  Axon guidance molecules in vascular patterning. , 2010, Cold Spring Harbor perspectives in biology.

[64]  M. Skobe,et al.  Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. , 2007, The Journal of clinical investigation.

[65]  D. Ribatti.  Genetic and epigenetic mechanisms in the early development of the vascular system , 2006, Journal of anatomy.

[66]  Aleksander S. Popel,et al.  Elongation, proliferation & migration differentiate endothelial cell phenotypes and determine capillary sprouting , 2009, BMC Systems Biology.

[67]  R. Bronson,et al.  Essential Role of Endothelial Notch1 in Angiogenesis , 2005, Circulation.

[68]  John Calvin Reed,et al.  Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro. , 2000, The American journal of pathology.

[69]  P. Carmeliet,et al.  Common mechanisms of nerve and blood vessel wiring , 2005, Nature.

[70]  P. Burri,et al.  Optimality in the developing vascular system: Branching remodeling by means of intussusception as an efficient adaptation mechanism , 2002, Developmental dynamics : an official publication of the American Association of Anatomists.

[71]  L. Reid,et al.  The effect of continued hypoxia on rat pulmonary arterial circulation. An ultrastructural study. , 1978, Laboratory investigation; a journal of technical methods and pathology.

[72]  Roeland M. H. Merks,et al.  Cell elongation is key to in silico replication of in vitro vasculogenesis and subsequent remodeling. , 2006, Developmental biology.

[73]  G. Thurston,et al.  Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting , 2007, Proceedings of the National Academy of Sciences.

[74]  Gavin Thurston,et al.  Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[75]  Elizabeth A V Jones,et al.  The initiation of blood flow and flow induced events in early vascular development. , 2011, Seminars in cell & developmental biology.

[76]  Stuart K Williams,et al.  Capillary endothelial cell cultures: phenotypic modulation by matrix components , 1983, The Journal of cell biology.

[77]  S A Tschanz,et al.  Intussusceptive angiogenesis: its role in embryonic vascular network formation. , 2000, Circulation research.

[78]  A. Garner,et al.  Degeneration of Intramural Pericytes in Diabetic Retinopathy , 1970, British medical journal.

[79]  E. Dejana,et al.  Endothelial cadherins and tumor angiogenesis. , 2006, Experimental cell research.

[80]  J. Bloodworth,et al.  Diabetic Amyotrophy: Light and Electron Microscopic Investigation , 1967, Diabetes.

[81]  J. Folkman,et al.  Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. , 1977, Microvascular research.

[82]  Ke-shu Xu,et al.  Tubulogenesis during blood vessel formation. , 2011, Seminars in cell & developmental biology.

[83]  D. Sheppard,et al.  Integrin-α9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis , 2009, Developmental cell.

[84]  A. Ridley,et al.  Cell structure and dynamics. , 2011, Current opinion in cell biology.

[85]  Paul A. Bates,et al.  Tipping the Balance: Robustness of Tip Cell Selection, Migration and Fusion in Angiogenesis , 2009, PLoS Comput. Biol..

[86]  J. Kitajewski,et al.  Tips, stalks, tubes: notch-mediated cell fate determination and mechanisms of tubulogenesis during angiogenesis. , 2012, Cold Spring Harbor perspectives in medicine.

[87]  Frederik De Smet,et al.  Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization , 2009, Cell.

[88]  K. Alitalo,et al.  VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia , 2003, The Journal of cell biology.

[89]  R. Jain,et al.  Vascular Morphogenesis and Remodeling in a Model of Tissue Repair: Blood Vessel Formation and Growth in the Ovarian Pedicle After Ovariectomy , 2001, Circulation research.

[90]  M. Iruela-Arispe,et al.  Notch signaling in blood vessels: who is talking to whom about what? , 2007, Circulation research.

[91]  Detlev Drenckhahn,et al.  Pericyte involvement in capillary sprouting during angiogenesis in situ , 1992, Cell and Tissue Research.

[92]  G. Thurston,et al.  VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis , 2008, British Journal of Cancer.

[93]  George E. Davis,et al.  Endothelial tubes assemble from intracellular vacuoles in vivo , 2006, Nature.

[94]  Peter Carmeliet,et al.  Mechanisms of Vessel Branching: Filopodia on Endothelial Tip Cells Lead the Way , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[95]  Holger Gerhardt,et al.  Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. , 2009, Developmental cell.

[96]  R. Mecham,et al.  Cellular and molecular mechanisms of pulmonary vascular remodeling. , 1997, Annual review of physiology.

[97]  K. Friedrich,et al.  Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor beta signaling. , 2008, Cancer research.

[98]  Victoria L. Bautch,et al.  The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching , 2008, The Journal of cell biology.

[99]  R. Hynes,et al.  Embryonic mesodermal defects in alpha 5 integrin-deficient mice. , 1993, Development.

[100]  E. Keshet,et al.  A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. , 1998, Development.

[101]  B R Johansson,et al.  Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. , 1997, Science.

[102]  G. Davis,et al.  Extracellular matrix mediates a molecular balance between vascular morphogenesis and regression , 2008, Current opinion in hematology.

[103]  Yukiko Kurihara,et al.  Angiogenic morphogenesis driven by dynamic and heterogeneous collective endothelial cell movement , 2011, Development.

[104]  Gavin Thurston,et al.  The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth , 2007, Nature Reviews Cancer.

[105]  Holger Gerhardt,et al.  Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. , 2002, Genes & development.

[106]  L. Brown,et al.  A direct role of dopamine in the rat subthalamic nucleus and an adjacent intrapeduncular area. , 1979, Science.

[107]  J. Stone,et al.  Mechanisms of retinal angiogenesis , 1997, Progress in Retinal and Eye Research.

[108]  M. Tessier-Lavigne,et al.  Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function , 2003, Nature.

[109]  B. Weinstein,et al.  Angiogenic network formation in the developing vertebrate trunk , 2003, Development.

[110]  G. Davis,et al.  An alpha 2 beta 1 integrin-dependent pinocytic mechanism involving intracellular vacuole formation and coalescence regulates capillary lumen and tube formation in three-dimensional collagen matrix. , 1996, Experimental cell research.

[111]  F. Sabin.  Studies on the origin of blood vessels and of red corpuscles as seen in the living blastoderm of the chick during the second day of incubation , 1920 .

[112]  W. Risau,et al.  Mechanisms of angiogenesis , 1997, Nature.

[113]  D. Cogan,et al.  The mural cell in perspective. , 1967, Archives of ophthalmology.

[114]  Marcus Fruttiger,et al.  Development of the retinal vasculature , 2007, Angiogenesis.

[115]  S. Patel-Hett,et al.  Signal transduction in vasculogenesis and developmental angiogenesis. , 2011, The International journal of developmental biology.

[116]  H. Kleinman,et al.  Intracellular mechanisms involved in basement membrane induced blood vessel differentiation in vitro , 1991, In Vitro Cellular & Developmental Biology - Animal.

[117]  E. Dejana,et al.  Perspectives Series: Cell Adhesion in Vascular Biology Endothelial Adherens Junctions: Implications in the Control of Vascular Permeability and Angiogenesis , 1996 .

[118]  Elisabetta Dejana,et al.  The molecular basis of vascular lumen formation in the developing mouse aorta. , 2009, Developmental cell.

[119]  I. Geudens,et al.  Coordinating cell behaviour during blood vessel formation , 2011, Development.

[120]  B. Weinstein,et al.  In vivo imaging of embryonic vascular development using transgenic zebrafish. , 2002, Developmental biology.

[121]  Chenghua Gu,et al.  Semaphorin 3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism. , 2011, Genes & development.

[122]  Andrew P. McMahon,et al.  Canonical Wnt Signaling Regulates Organ-Specific Assembly and Differentiation of CNS Vasculature , 2008, Science.

[123]  T. Billroth.  Untersuchungen über die Entwicklung der Blutgefässe nebst Beobachtungen aus der Königlichen chirurgischen Universitäts-Klinik zu Berlin , 1856 .

[124]  Li Yuan,et al.  Flow regulates arterial-venous differentiation in the chick embryo yolk sac , 2003, Development.

[125]  Marcus Fruttiger,et al.  Periodic Delta-like 4 expression in developing retinal arteries. , 2004, Gene expression patterns : GEP.

[126]  Eliot R. Clark,et al.  Studies on the growth of blood-vessels in the tail of the frog larva—by observation and experiment on the living animal , 1918 .

[127]  N. Ashton.  Oxygen and the growth and development of retinal vessels. In vivo and in vitro studies. The XX Francis I. Proctor Lecture. , 1966, American journal of ophthalmology.

[128]  Holger Gerhardt,et al.  Neuropilin‐1 is required for endothelial tip cell guidance in the developing central nervous system , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[129]  R. Adams,et al.  Dynamics of endothelial cell behavior in sprouting angiogenesis. , 2010, Current opinion in cell biology.

[130]  M. Gertsenstein,et al.  Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. , 1994, Genes & development.

[131]  V. Nehls,et al.  Guided migration as a novel mechanism of capillary network remodeling is regulated by basic fibroblast growth factor , 1998, Histochemistry and Cell Biology.

[132]  Christopher C W Hughes,et al.  Cell‐autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[133]  V. Bautch,et al.  Vascular development: genetic mechanisms and links to vascular disease. , 2010, Current topics in developmental biology.

[134]  R. Auerbach,et al.  Angiogenesis in the mouse cornea. , 1979, Science.

[135]  G. Davis,et al.  The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices. , 2002, Journal of cell science.

[136]  Pamela F. Jones,et al.  Isolation of Angiopoietin-1, a Ligand for the TIE2 Receptor, by Secretion-Trap Expression Cloning , 1996, Cell.

[137]  Joseph B. Kearney,et al.  In vitro differentiation of mouse ES cells: hematopoietic and vascular development. , 2003, Methods in enzymology.

[138]  Christiana Ruhrberg,et al.  Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. , 2010, Blood.

[139]  Amber N. Stratman,et al.  In vitro three dimensional collagen matrix models of endothelial lumen formation during vasculogenesis and angiogenesis. , 2008, Methods in enzymology.

[140]  Holger Gerhardt,et al.  Angiogenesis: a team effort coordinated by notch. , 2009, Developmental cell.

[141]  Markus Affolter,et al.  Complex cell rearrangements during intersegmental vessel sprouting and vessel fusion in the zebrafish embryo. , 2008, Developmental biology.

[142]  Ulrich Berge,et al.  ROCK-mediated contractility, tight junctions and channels contribute to the conversion of a preapical patch into apical surface during isochoric lumen initiation , 2008, Journal of Cell Science.

[143]  H. Schnürch,et al.  Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. , 1993, Development.

[144]  D. Ribatti,et al.  A brief history of angiogenesis assays. , 2011, The International journal of developmental biology.

[145]  J. Ash,et al.  Lens-specific VEGF-A expression induces angioblast migration and proliferation and stimulates angiogenic remodeling. , 2000, Developmental biology.

[146]  Paul McLoughlin,et al.  The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis? , 2002, Journal of anatomy.