Array ( [0] => {{Short description|Blood vessel formation, when new vessels emerge from existing vessels}} [1] => {{Distinguish|vasculogenesis}} [2] => {{cs1 config|name-list-style=vanc}} [3] => {{Infobox embryology [4] => |Name = Angiogenesis [5] => |Latin = [6] => |Image = Angiogenesis.png [7] => |Caption = Angiogenesis following vasculogenesis [8] => }} [9] => [[File:Angiogenesis medical animation still.jpg|thumb|263x263px|3D medical animation still showing angiogenesis]] [10] => '''Angiogenesis''' is the physiological process through which new [[blood vessel]]s form from pre-existing vessels,{{cite book | veditors = Santulli G | title=Angiogenesis insights from a systematic overview | publisher=Nova Science | location=New York | year=2013 | isbn=978-1-62618-114-4 }}{{cite journal | vauthors = Dudley AC, Griffioen AW | title = Pathological angiogenesis: mechanisms and therapeutic strategies | journal = Angiogenesis | volume = 26 | issue = 3 | pages = 313–347 | date = August 2023 | pmid = 37060495 | pmc = 10105163 | doi = 10.1007/s10456-023-09876-7 }}{{cite journal | vauthors = Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O | title = Type-2 pericytes participate in normal and tumoral angiogenesis | journal = American Journal of Physiology. Cell Physiology | volume = 307 | issue = 1 | pages = C25–C38 | date = July 2014 | pmid = 24788248 | pmc = 4080181 | doi = 10.1152/ajpcell.00084.2014 }} formed in the earlier stage of [[vasculogenesis]]. Angiogenesis continues the growth of the [[circulatory system|vasculature]] mainly by processes of sprouting and splitting, but processes such as [[coalescent angiogenesis]],{{cite journal | vauthors = Nitzsche B, Rong WW, Goede A, Hoffmann B, Scarpa F, Kuebler WM, Secomb TW, Pries AR | display-authors = 6 | title = Coalescent angiogenesis-evidence for a novel concept of vascular network maturation | journal = Angiogenesis | volume = 25 | issue = 1 | pages = 35–45 | date = February 2022 | pmid = 34905124 | doi = 10.1007/s10456-021-09824-3 | pmc = 8669669 }} vessel elongation and vessel cooption also play a role. Vasculogenesis is the [[embryogenesis|embryonic]] formation of [[endothelium|endothelial]] cells from [[mesoderm]] cell precursors,{{cite journal | vauthors = Risau W, Flamme I | title = Vasculogenesis | journal = Annual Review of Cell and Developmental Biology | volume = 11 | pages = 73–91 | year = 1995 | pmid = 8689573 | doi = 10.1146/annurev.cb.11.110195.000445 }} and from [[neovascularization]], although discussions are not always precise (especially in older texts). The first vessels in the developing [[embryo]] form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during [[embryogenesis|development]] and in disease.{{cite journal | vauthors = Flamme I, Frölich T, Risau W | title = Molecular mechanisms of vasculogenesis and embryonic angiogenesis | journal = Journal of Cellular Physiology | volume = 173 | issue = 2 | pages = 206–210 | date = November 1997 | pmid = 9365523 | doi = 10.1002/(SICI)1097-4652(199711)173:2<206::AID-JCP22>3.0.CO;2-C | s2cid = 36723610 }} [11] => [12] => Angiogenesis is a normal and vital process in growth and development, as well as in [[wound healing]] and in the formation of [[granulation tissue]]. However, it is also a fundamental step in the transition of [[tumor]]s from a benign state to a [[malignant]] one, leading to the use of [[angiogenesis inhibitor]]s in the treatment of [[cancer]].{{cite book | vauthors = Milosevic V, Edelmann RJ, Fosse JH, Östman A, Akslen LA | chapter = Molecular Phenotypes of Endothelial Cells in Malignant Tumors |date=2022 | veditors = Akslen LA, Watnick RS | title =Biomarkers of the Tumor Microenvironment |pages=31–52 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-030-98950-7_3 |isbn=978-3-030-98950-7 }} The essential role of angiogenesis in tumor growth was first proposed in 1971 by [[Judah Folkman]], who described tumors as "hot and bloody,"{{cite book| vauthors = Penn JS |title=Retinal and Choroidal Angiogenesis|url=https://books.google.com/books?id=Y-26TIIROYwC&pg=PA119|access-date=26 June 2010|date=11 March 2008|publisher=Springer|isbn=978-1-4020-6779-2|pages=119–}} illustrating that, at least for many tumor types, flush [[perfusion]] and even [[hyperaemia|hyperemia]] are characteristic. [13] => [14] => ==Types== [15] => [16] => ===Sprouting angiogenesis=== [17] => Sprouting angiogenesis was the first identified form of angiogenesis and because of this, it is much more understood than intussusceptive angiogenesis. It occurs in several well-characterized stages. The initial signal comes from tissue areas that are devoid of vasculature. The [[Hypoxia (medical)|hypoxia]] that is noted in these areas causes the tissues to demand the presence of nutrients and oxygen that will allow the tissue to carry out metabolic activities. Because of this, parenchymal cells will secrete vascular endothelial growth factor ([[VEGF-A]]) which is a proangiogenic growth factor.Adair TH, Montani JP. Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences; 2010. Chapter 1, Overview of Angiogenesis. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53238/ These biological signals activate [[receptor (biochemistry)|receptor]]s on [[endothelial cell]]s present in pre-existing blood vessels. Second, the activated endothelial cells, also known as '''tip cells''',{{cite journal | vauthors = Weavers H, Skaer H | title = Tip cells: master regulators of tubulogenesis? | journal = Seminars in Cell & Developmental Biology | volume = 31 | issue = 100 | pages = 91–99 | date = July 2014 | pmid = 24721475 | pmc = 4071413 | doi = 10.1016/j.semcdb.2014.04.009 }} begin to release [[enzyme]]s called [[protease]]s that degrade the [[basement membrane]] to allow endothelial cells to escape from the original (parent) vessel walls. The [[endothelial cell]]s then [[cell growth|proliferate]] into the surrounding [[Matrix (biology)|matrix]] and form solid sprouts connecting neighboring vessels. The cells that are proliferating are located behind the tip cells and are known as '''stalk cells'''. The proliferation of these cells allows the capillary sprout to grow in length simultaneously. [18] => [19] => As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in [[tandem]], using adhesion molecules called [[integrin]]s. These sprouts then form loops to become a full-fledged vessel [[lumen (anatomy)|lumen]] as cells migrate to the site of angiogenesis. Sprouting occurs at a rate of several millimeters per day, and enables new vessels to grow across gaps in the [[vasculature]]. It is markedly different from splitting angiogenesis because it forms entirely new vessels as opposed to splitting existing vessels. [20] => [21] => ===Intussusceptive angiogenesis=== [22] => {{main|Intussusceptive angiogenesis}} [23] => [[Intussusceptive angiogenesis]], also known as ''splitting angiogenesis'', is the formation of a new blood vessel by splitting an existing blood vessel into two. [24] => [25] => Intussusception was first observed in [[neonatal]] rats. In this type of vessel formation, the capillary wall extends into the [[lumen (anatomy)|lumen]] to split a single vessel in two. There are four phases of intussusceptive angiogenesis. First, the two opposing capillary walls establish a zone of contact. Second, the [[endothelial]] [[cell junction]]s are reorganized and the vessel [[bilayer]] is [[perforated]] to allow [[growth factors]] and cells to penetrate into the lumen. Third, a core is formed between the 2 new vessels at the zone of contact that is filled with [[pericyte]]s and [[myofibroblast]]s. These cells begin laying [[collagen]] fibers into the core to provide an [[extracellular matrix]] for growth of the vessel lumen. Finally, the core is fleshed out with no alterations to the basic structure. Intussusception is important because it is a reorganization of existing cells. It allows a vast increase in the number of [[capillaries]] without a corresponding increase in the number of [[endothelial cell]]s. This is especially important in embryonic development as there are not enough resources to create a rich [[Microcirculation|microvasculature]] with new cells every time a new vessel develops.{{cite journal | vauthors = Burri PH, Hlushchuk R, Djonov V | title = Intussusceptive angiogenesis: its emergence, its characteristics, and its significance | journal = Developmental Dynamics | volume = 231 | issue = 3 | pages = 474–488 | date = November 2004 | pmid = 15376313 | doi = 10.1002/dvdy.20184 | s2cid = 35018922 | doi-access = free }} [26] => [27] => ===Coalescent angiogenesis=== [28] => {{main|Coalescent angiogenesis}} [29] => [[Coalescent angiogenesis]] is a mode of angiogenesis, considered to be the opposite of intussusceptive angiogenesis, where capillaries fuse, or coalesce, to make a larger bloodvessel, thereby increasing blood flow and circulation.{{cite journal | vauthors = Nitzsche B, Rong WW, Goede A, Hoffmann B, Scarpa F, Kuebler WM, Secomb TW, Pries AR | display-authors = 6 | title = Coalescent angiogenesis-evidence for a novel concept of vascular network maturation | journal = Angiogenesis | volume = 25 | issue = 1 | pages = 35–45 | date = February 2022 | pmid = 34905124 | pmc = 8669669 | doi = 10.1007/s10456-021-09824-3 }} Coalescent angiogenesis has extended out of the domain of embryology. It is assumed to play a role in the formation of neovasculature, such as in a tumor.{{cite journal | vauthors = Pezzella F, Kerbel RS | title = On coalescent angiogenesis and the remarkable flexibility of blood vessels | journal = Angiogenesis | volume = 25 | issue = 1 | pages = 1–3 | date = February 2022 | pmid = 34993716 | doi = 10.1007/s10456-021-09825-2 | s2cid = 254188870 | doi-access = free }} [30] => [31] => ==Physiology== [32] => [33] => ===Mechanical stimulation=== [34] => Mechanical stimulation of angiogenesis is not well characterized. There is a significant amount of controversy with regard to [[shear stress]] acting on capillaries to cause angiogenesis, although current knowledge suggests that increased muscle contractions may increase angiogenesis.{{cite journal | vauthors = Prior BM, Yang HT, Terjung RL | title = What makes vessels grow with exercise training? | journal = Journal of Applied Physiology | volume = 97 | issue = 3 | pages = 1119–1128 | date = September 2004 | pmid = 15333630 | doi = 10.1152/japplphysiol.00035.2004 }} This may be due to an increase in the production of [[nitric oxide]] during exercise. Nitric oxide results in vasodilation of blood vessels. [35] => [36] => ===Chemical stimulation=== [37] => Chemical stimulation of angiogenesis is performed by various angiogenic proteins e.g. integrins and prostaglandins, including several [[growth factor]]s e.g. VEGF, FGF. [38] => [39] => ====Overview==== [40] => {|class="wikitable" [41] => |- [42] => ! Stimulator !! Mechanism [43] => |- [44] => | [[fibroblast growth factor|FGF]] || Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts [45] => |- [46] => | [[vascular endothelial growth factor|VEGF]] || Affects permeability [47] => |- [48] => | [[VEGFR]] and [[NRP-1]] || Integrate survival signals [49] => |- [50] => | [[Ang1]] and [[Ang2]] || Stabilize vessels [51] => |- [52] => | [[platelet derived growth factor|PDGF]] (BB-homodimer) and [[PDGFR]] || recruit [[smooth muscle cell]]s [53] => |- [54] => | [[transforming growth factor beta|TGF-β]], [[endoglin]] and [[transforming growth factor beta receptor|TGF-β receptor]]s || ↑[[extracellular matrix]] production [55] => |- [56] => | [[CCL2]] ||Recruits [[lymphocyte]]s to sites of [[inflammation]] [57] => |- [58] => | [[Histamine]] || [59] => |- [60] => | Integrins [[alpha-v beta-3|αVβ3]], [[alpha-v beta-5|αVβ5]] (?Perhaps an inhibitor of angiogenesis: {{cite journal | vauthors = Sheppard D | title = Endothelial integrins and angiogenesis: not so simple anymore | journal = The Journal of Clinical Investigation | volume = 110 | issue = 7 | pages = 913–914 | date = October 2002 | pmid = 12370267 | pmc = 151161 | doi = 10.1172/JCI16713 }}) and [[alpha-5 beta-1|α5β1]] || Bind [[matrix macromolecules]] and [[proteinase]]s [61] => |- [62] => | [[VE-cadherin]] and [[CD31]] || endothelial [[junctional molecule]]s [63] => |- [64] => | [[ephrin]] || Determine formation of arteries or veins [65] => |- [66] => | [[plasminogen activator]]s || remodels [[extracellular matrix]], releases and activates growth factors [67] => |- [68] => | [[plasminogen activator inhibitor-1]] || stabilizes nearby vessels [69] => |- [70] => | [[nitric oxide synthase|eNOS]] and [[COX-2]] || [71] => |- [72] => | [[AC133]] || regulates [[angioblast]] differentiation [73] => |- [74] => | [[ID1]]/[[ID3 (gene)|ID3]] || Regulates endothelial [[transdifferentiation]] [75] => |- [76] => |Class 3 [[semaphorin]]s [77] => |Modulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeability{{cite journal | vauthors = Mecollari V, Nieuwenhuis B, Verhaagen J | title = A perspective on the role of class III semaphorin signaling in central nervous system trauma | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 328 | date = 2014 | pmid = 25386118 | pmc = 4209881 | doi = 10.3389/fncel.2014.00328 | doi-access = free }} [78] => |- [79] => |Nogo-A ||Regulates endothelial cell migration and proliferation.{{cite journal | vauthors = Rust R, Grönnert L, Gantner C, Enzler A, Mulders G, Weber RZ, Siewert A, Limasale YD, Meinhardt A, Maurer MA, Sartori AM, Hofer AS, Werner C, Schwab ME | display-authors = 6 | title = Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 28 | pages = 14270–14279 | date = July 2019 | pmid = 31235580 | pmc = 6628809 | doi = 10.1073/pnas.1905309116 | doi-access = free | bibcode = 2019PNAS..11614270R }} Alters vascular permeability.{{cite journal | vauthors = Rust R, Weber RZ, Grönnert L, Mulders G, Maurer MA, Hofer AS, Sartori AM, Schwab ME | display-authors = 6 | title = Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 20040 | date = December 2019 | pmid = 31882970 | pmc = 6934709 | doi = 10.1038/s41598-019-56634-1 | bibcode = 2019NatSR...920040R | doi-access = free }} [80] => |} [81] => [82] => ====FGF==== [83] => {{Further|Fibroblast growth factor}} [84] => [85] => The [[fibroblast growth factor]] (FGF) family with its prototype members [[FGF-1]] (acidic FGF) and [[FGF-2]] (basic FGF) consists to date of at least 22 known members.{{cite journal | vauthors = Ornitz DM, Itoh N | title = Fibroblast growth factors | journal = Genome Biology | volume = 2 | issue = 3 | pages = REVIEWS3005 | year = 2001 | pmid = 11276432 | pmc = 138918 | doi = 10.1186/gb-2001-2-3-reviews3005 | doi-access = free }} Most are single-chain peptides of 16-18 kDa and display high affinity to heparin and heparan sulfate. In general, FGFs stimulate a variety of cellular functions by binding to cell surface FGF-receptors in the presence of heparin proteoglycans. The FGF-receptor family is composed of seven members, and all the receptor proteins are single-chain receptor tyrosine kinases that become activated through autophosphorylation induced by a mechanism of FGF-mediated receptor dimerization. Receptor activation gives rise to a signal transduction cascade that leads to gene activation and diverse biological responses, including cell differentiation, proliferation, and matrix dissolution, thus initiating a process of mitogenic activity critical for the growth of endothelial cells, fibroblasts, and smooth muscle cells. [86] => FGF-1, unique among all 22 members of the FGF family, can bind to all seven FGF-receptor subtypes, making it the broadest-acting member of the FGF family, and a potent mitogen for the diverse cell types needed to mount an angiogenic response in damaged (hypoxic) tissues, where upregulation of FGF-receptors occurs.{{cite journal | vauthors = Blaber M, DiSalvo J, Thomas KA | title = X-ray crystal structure of human acidic fibroblast growth factor | journal = Biochemistry | volume = 35 | issue = 7 | pages = 2086–2094 | date = February 1996 | pmid = 8652550 | doi = 10.1021/bi9521755 | citeseerx = 10.1.1.660.7607 }} FGF-1 stimulates the proliferation and differentiation of all cell types necessary for building an arterial vessel, including endothelial cells and smooth muscle cells; this fact ''distinguishes FGF-1 from other pro-angiogenic growth factors'', such as [[vascular endothelial growth factor]] (VEGF), which primarily drives the formation of new capillaries.{{cite journal | vauthors = Khurana R, Simons M | title = Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease | journal = Trends in Cardiovascular Medicine | volume = 13 | issue = 3 | pages = 116–122 | date = April 2003 | pmid = 12691676 | doi = 10.1016/S1050-1738(02)00259-1 }} [87] => [88] => Besides FGF-1, one of the most important functions of fibroblast growth factor-2 (FGF-2 or [[bFGF]]) is the promotion of endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures, thus promoting angiogenesis. FGF-2 is a more potent angiogenic factor than VEGF or PDGF ([[platelet-derived growth factor]]); however, it is less potent than FGF-1. As well as stimulating blood vessel growth, aFGF (FGF-1) and bFGF (FGF-2) are important players in wound healing. They stimulate the proliferation of fibroblasts and endothelial cells that give rise to angiogenesis and developing granulation tissue; both increase blood supply and fill up a wound space/cavity early in the wound-healing process. [89] => [90] => ====VEGF==== [91] => [[Vascular endothelial growth factor]] (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network. Initial ''in vitro'' studies demonstrated bovine capillary endothelial cells will proliferate and show signs of tube structures upon stimulation by VEGF and [[bFGF]], although the results were more pronounced with VEGF.{{cite journal | vauthors = Goto F, Goto K, Weindel K, Folkman J | title = Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 69 | issue = 5 | pages = 508–517 | date = November 1993 | pmid = 8246443 }} Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries.{{cite journal | vauthors = Ding YH, Luan XD, Li J, Rafols JA, Guthinkonda M, Diaz FG, Ding Y | title = Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke | journal = Current Neurovascular Research | volume = 1 | issue = 5 | pages = 411–420 | date = December 2004 | pmid = 16181089 | doi = 10.2174/1567202043361875 | url = http://www.bentham-direct.org/pages/content.php?CNR/2004/00000001/00000005/003AG.SGM | url-status = dead | s2cid = 22015361 | archive-url = https://web.archive.org/web/20120419004150/http://www.bentham-direct.org/pages/content.php?CNR%2F2004%2F00000001%2F00000005%2F003AG.SGM | archive-date = April 19, 2012 }}{{cite journal | vauthors = Gavin TP, Robinson CB, Yeager RC, England JA, Nifong LW, Hickner RC | title = Angiogenic growth factor response to acute systemic exercise in human skeletal muscle | journal = Journal of Applied Physiology | volume = 96 | issue = 1 | pages = 19–24 | date = January 2004 | pmid = 12949011 | doi = 10.1152/japplphysiol.00748.2003 | s2cid = 12750224 }}{{cite journal | vauthors = Kraus RM, Stallings HW, Yeager RC, Gavin TP | title = Circulating plasma VEGF response to exercise in sedentary and endurance-trained men | journal = Journal of Applied Physiology | volume = 96 | issue = 4 | pages = 1445–1450 | date = April 2004 | pmid = 14660505 | doi = 10.1152/japplphysiol.01031.2003 | s2cid = 21090407 }}{{cite journal | vauthors = Lloyd PG, Prior BM, Yang HT, Terjung RL | title = Angiogenic growth factor expression in rat skeletal muscle in response to exercise training | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 284 | issue = 5 | pages = H1668–H1678 | date = May 2003 | pmid = 12543634 | doi = 10.1152/ajpheart.00743.2002 }} ''In vitro'' studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries. [92] => VEGF causes a massive signaling cascade in [[endothelium|endothelial]] cells. Binding to VEGF receptor-2 (VEGFR-2) starts a tyrosine kinase signaling cascade that stimulates the production of factors that variously stimulate vessel permeability (eNOS, producing NO), proliferation/survival (bFGF), migration (ICAMs/VCAMs/MMPs) and finally differentiation into mature blood vessels. Mechanically, VEGF is upregulated with muscle contractions as a result of increased blood flow to affected areas. The increased flow also causes a large increase in the [[mRNA]] production of VEGF receptors 1 and 2. The increase in receptor production means muscle contractions could cause upregulation of the signaling cascade relating to angiogenesis. As part of the angiogenic signaling cascade, NO is widely considered to be a major contributor to the angiogenic response because inhibition of NO significantly reduces the effects of angiogenic growth factors. However, inhibition of NO during exercise does not inhibit angiogenesis, indicating there are other factors involved in the angiogenic response. [93] => [94] => ====Angiopoietins==== [95] => The [[angiopoietins]], Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse [[Gene knockout|knock out]] studies.{{cite journal | vauthors = Thurston G | title = Role of Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis | journal = Cell and Tissue Research | volume = 314 | issue = 1 | pages = 61–68 | date = October 2003 | pmid = 12915980 | doi = 10.1007/s00441-003-0749-6 | s2cid = 2529783 }} [[Ang1]] and [[Ang2]] are protein growth factors which act by binding their receptors, [[Tie-1]] and [[Tie-2]]; while this is somewhat controversial, it seems that cell signals are transmitted mostly by [[Tie-2]]; though some papers show physiologic signaling via [[Tie-1]] as well. These receptors are [[tyrosine kinases]]. Thus, they can initiate [[cell signaling]] when ligand binding causes a dimerization that initiates [[phosphorylation]] on key tyrosines. [96] => [97] => ====MMP==== [98] => Another major contributor to angiogenesis is [[matrix metalloproteinase]] (MMP). MMPs help degrade the proteins that keep the vessel walls solid. This [[proteolysis]] allows the [[endothelial cell]]s to escape into the interstitial matrix as seen in sprouting angiogenesis. Inhibition of MMPs prevents the formation of new [[capillaries]].{{cite journal | vauthors = Haas TL, Milkiewicz M, Davis SJ, Zhou AL, Egginton S, Brown MD, Madri JA, Hudlicka O | display-authors = 6 | title = Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 279 | issue = 4 | pages = H1540–H1547 | date = October 2000 | pmid = 11009439 | doi = 10.1152/ajpheart.2000.279.4.H1540 | s2cid = 2543076 }} These [[enzyme]]s are highly regulated during the vessel formation process because destruction of the [[extracellular matrix]] would decrease the integrity of the microvasculature. [99] => [100] => ====Dll4==== [101] => [[DLL4|Delta-like ligand 4]] (Dll4) is a protein with a negative regulatory effect on angiogenesis.{{cite journal | vauthors = Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ | title = Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 9 | pages = 3219–3224 | date = February 2007 | pmid = 17296940 | pmc = 1805530 | doi = 10.1073/pnas.0611206104 | doi-access = free | bibcode = 2007PNAS..104.3219L }}{{cite journal | vauthors = Hellström M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalén M, Gerhardt H, Betsholtz C | display-authors = 6 | title = Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis | journal = Nature | volume = 445 | issue = 7129 | pages = 776–780 | date = February 2007 | pmid = 17259973 | doi = 10.1038/nature05571 | s2cid = 4407198 | bibcode = 2007Natur.445..776H }} Dll4 is a transmembrane ligand, for the [[notch family of receptors]]. There have been many studies conducted that have served to determine consequences of the Delta-like Ligand 4. One study in particular evaluated the effects of Dll4 on tumor vascularity and growth.{{cite journal | vauthors = Segarra M, Williams CK, Sierra Mde L, Bernardo M, McCormick PJ, Maric D, Regino C, Choyke P, Tosato G | display-authors = 6 | title = Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth | journal = Blood | volume = 112 | issue = 5 | pages = 1904–11 | date = September 2008 | pmid = 18577711 | pmc = 2518892 | doi = 10.1182/blood-2007-11-126045 }} In order for a tumor to grow and develop, it must have the proper vasculature. The VEGF pathway is vital to the development of vasculature that in turn, helps the tumors to grow. The combined blockade of VEGF and Dll4 results in the inhibition of tumor progression and angiogenesis throughout the tumor. This is due to the hindrance of signaling in endothelial cell signaling which cuts off the proliferation and sprouting of these endothelial cells. With this inhibition, the cells do not uncontrollably grow, therefore, the cancer is stopped at this point. if the blockade, however, were to be lifted, the cells would begin their proliferation once again.{{cite journal | vauthors = Lee D, Kim D, Choi YB, Kang K, Sung ES, Ahn JH, Goo J, Yeom DH, Jang HS, Moon KD, Lee SH, You WK | display-authors = 6 | title = Simultaneous blockade of VEGF and Dll4 by HD105, a bispecific antibody, inhibits tumor progression and angiogenesis | journal = mAbs | volume = 8 | issue = 5 | pages = 892–904 | date = July 2016 | pmid = 27049350 | pmc = 4968104 | doi = 10.1080/19420862.2016.1171432 | doi-access = free }} [102] => [103] => ==== Class 3 semaphorins ==== [104] => [[Semaphorin#Classes|Class 3 semaphorin]]s (SEMA3s) regulate angiogenesis by modulating [[endothelial cells|endothelial cell]] adhesion, migration, proliferation, survival and the recruitment of [[pericyte]]s. Furthermore, [[semaphorin]]s can interfere with VEGF-mediated angiogenesis since both SEMA3s and [[VEGF-A]] compete for [[neuropilin]] receptor binding at endothelial cells.{{cite journal | vauthors = Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M | title = Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor | journal = Cell | volume = 92 | issue = 6 | pages = 735–745 | date = March 1998 | pmid = 9529250 | doi = 10.1016/s0092-8674(00)81402-6 | s2cid = 547080 | doi-access = free }}{{cite journal | vauthors = Herzog B, Pellet-Many C, Britton G, Hartzoulakis B, Zachary IC | title = VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation | journal = Molecular Biology of the Cell | volume = 22 | issue = 15 | pages = 2766–2776 | date = August 2011 | pmid = 21653826 | pmc = 3145551 | doi = 10.1091/mbc.E09-12-1061 }} The relative expression levels of SEMA3s and VEGF-A may therefore be important for angiogenesis. [105] => [106] => ===Chemical inhibition=== [107] => {{Main|Angiogenesis inhibitor}} [108] => [109] => An [[angiogenesis inhibitor]] can be endogenous or come from outside as [[medication|drug]] or a [[diet (nutrition)|dietary component]]. [110] => [111] => ==Application in medicine== [112] => [113] => ===Angiogenesis as a therapeutic target=== [114] => Angiogenesis may be a target for combating diseases such as [[heart disease]] characterized by either poor vascularisation or abnormal vasculature.{{cite journal | vauthors = Ferrara N, Kerbel RS | title = Angiogenesis as a therapeutic target | journal = Nature | volume = 438 | issue = 7070 | pages = 967–974 | date = December 2005 | pmid = 16355214 | doi = 10.1038/nature04483 | s2cid = 1183610 | bibcode = 2005Natur.438..967F }} Application of specific compounds that may inhibit or induce the creation of new [[blood vessels]] in the body may help combat such diseases. The presence of blood vessels where there should be none may affect the mechanical properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several diseases, such as [[ischemia|ischemic chronic wounds]], are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair. Other diseases, such as age-related [[macular degeneration]], may be created by a local expansion of blood vessels, interfering with normal physiological processes. [115] => [116] => The modern clinical application of the principle of angiogenesis can be divided into two main areas: anti-angiogenic therapies, which angiogenic research began with, and pro-angiogenic therapies. Whereas anti-angiogenic therapies are being employed to fight cancer and malignancies,{{cite journal | vauthors = Folkman J, Klagsbrun M | title = Angiogenic factors | journal = Science | volume = 235 | issue = 4787 | pages = 442–447 | date = January 1987 | pmid = 2432664 | doi = 10.1126/science.2432664 | bibcode = 1987Sci...235..442F }}{{cite journal | vauthors = Folkman J | title = Fighting cancer by attacking its blood supply | journal = Scientific American | volume = 275 | issue = 3 | pages = 150–154 | date = September 1996 | pmid = 8701285 | doi = 10.1038/scientificamerican0996-150 | bibcode = 1996SciAm.275c.150F }} which require an abundance of [[oxygen]] and nutrients to proliferate, pro-angiogenic therapies are being explored as options to treat [[cardiovascular diseases]], the number one cause of death in the [[Western world]]. One of the first applications of pro-angiogenic methods in humans was a German trial using fibroblast growth factor 1 (FGF-1) for the treatment of coronary artery disease.{{cite journal | vauthors = Stegmann TJ | title = FGF-1: a human growth factor in the induction of neoangiogenesis | journal = Expert Opinion on Investigational Drugs | volume = 7 | issue = 12 | pages = 2011–2015 | date = December 1998 | pmid = 15991943 | doi = 10.1517/13543784.7.12.2011 }}{{cite journal | vauthors = Stegmann TJ, Hoppert T, Schneider A, Gemeinhardt S, Köcher M, Ibing R, Strupp G | title = [Induction of myocardial neoangiogenesis by human growth factors. A new therapeutic approach in coronary heart disease] | language = de | journal = Herz | volume = 25 | issue = 6 | pages = 589–599 | date = September 2000 | pmid = 11076317 | doi = 10.1007/PL00001972 | s2cid = 21240045 }}{{cite journal | vauthors = Folkman J | title = Angiogenic therapy of the human heart | journal = Circulation | volume = 97 | issue = 7 | pages = 628–629 | date = February 1998 | pmid = 9495294 | doi = 10.1161/01.CIR.97.7.628 | doi-access = free }} [117] => [118] => Regarding the [[mechanism of action]], pro-angiogenic methods can be differentiated into three main categories: [[gene therapy]], targeting genes of interest for amplification or inhibition; [[protein replacement therapy]], which primarily manipulates angiogenic growth factors like [[FGF-1]] or [[vascular endothelial growth factor]], VEGF; and cell-based therapies, which involve the implantation of specific cell types. [119] => [120] => There are still serious, unsolved problems related to gene therapy. Difficulties include effective integration of the therapeutic genes into the genome of target cells, reducing the risk of an undesired immune response, potential toxicity, [[immunogenicity]], inflammatory responses, and [[oncogenesis]] related to the viral vectors used in implanting genes and the sheer complexity of the genetic basis of angiogenesis. The most commonly occurring disorders in humans, such as heart disease, high blood pressure, diabetes and [[Alzheimer's disease]], are most likely caused by the combined effects of variations in many genes, and, thus, injecting a single gene may not be significantly beneficial in such diseases.{{citation needed|date=August 2018}} [121] => [122] => By contrast, pro-angiogenic protein therapy uses well-defined, precisely structured proteins, with previously defined optimal doses of the individual protein for disease states, and with well-known biological effects. On the other hand, an obstacle of protein therapy is the mode of delivery. Oral, intravenous, intra-arterial, or intramuscular routes of protein administration are not always as effective, as the therapeutic protein may be metabolized or cleared before it can enter the target tissue. Cell-based pro-angiogenic therapies are still early stages of research, with many open questions regarding best cell types and dosages to use. [123] => [124] => ===Tumor angiogenesis=== [125] => [[File:Diagram showing why cancer cells need their own blood supply.svg|270px|thumb| Without angiogenesis a tumor cannot grow beyond a limited size]] [126] => Cancer cells are cells that have lost their ability to divide in a controlled fashion. A [[malignant tumor]] consists of a population of rapidly dividing and growing cancer cells that progressively accrues [[mutation]]s. However, tumors need a dedicated blood supply to provide the oxygen and other essential nutrients they require in order to grow beyond a certain size (generally 1–2 mm3).{{cite journal | vauthors = McDougall SR, Anderson AR, Chaplain MA | title = Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies | journal = Journal of Theoretical Biology | volume = 241 | issue = 3 | pages = 564–589 | date = August 2006 | pmid = 16487543 | doi = 10.1016/j.jtbi.2005.12.022 | bibcode = 2006JThBi.241..564M }}{{cite journal | vauthors = Spill F, Guerrero P, Alarcon T, Maini PK, Byrne HM | title = Mesoscopic and continuum modelling of angiogenesis | journal = Journal of Mathematical Biology | volume = 70 | issue = 3 | pages = 485–532 | date = February 2015 | pmid = 24615007 | pmc = 5320864 | doi = 10.1007/s00285-014-0771-1 | arxiv = 1401.5701 }} [127] => [128] => Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. [[Vascular endothelial growth factor|VEGF]]) and proteins. Growth factors such as [[bFGF]] and [[VEGF]] can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion. Unlike normal blood vessels, tumor blood vessels are dilated with an irregular shape.{{cite book | vauthors = Gonzalez-Perez RR, Rueda BR | title =Tumor angiogenesis regulators | date = 2013 | publisher = Taylor & Francis|location=Boca Raton | isbn = 978-1-4665-8097-8 | page = 347 | edition = first | url = https://books.google.com/books?id=jRTrabp4PMgC|access-date=2 October 2014}} Other clinicians believe angiogenesis really serves as a waste pathway, taking away the biological end products secreted by rapidly dividing cancer cells. In either case, angiogenesis is a necessary and required step for transition from a small harmless cluster of cells, often said to be about the size of the metal ball at the end of a ball-point pen, to a large tumor. Angiogenesis is also required for the spread of a tumor, or [[metastasis]]. Single cancer cells can break away from an established solid tumor, enter the blood vessel, and be carried to a distant site, where they can implant and begin the growth of a secondary tumor. Evidence now suggests the blood vessel in a given solid tumor may, in fact, be mosaic vessels, composed of [[endothelium|endothelial cells]] and tumor cells. This mosaicity allows for substantial shedding of tumor cells into the vasculature, possibly contributing to the appearance of [[circulating tumor cell]]s in the peripheral blood of patients with malignancies.{{cite journal | vauthors = Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW | display-authors = 6 | title = Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases | journal = Clinical Cancer Research | volume = 10 | issue = 20 | pages = 6897–6904 | date = October 2004 | pmid = 15501967 | doi = 10.1158/1078-0432.CCR-04-0378 | doi-access = free }} The subsequent growth of such metastases will also require a supply of nutrients and [[oxygen]] and a waste disposal pathway. [129] => [130] => Endothelial cells have long been considered genetically more stable than cancer cells. This genomic stability confers an advantage to targeting endothelial cells using antiangiogenic therapy, compared to [[chemotherapy]] directed at cancer cells, which rapidly mutate and acquire [[drug resistance]] to treatment. For this reason, [[endothelial cells]] are thought to be an ideal target for therapies directed against them.{{cite journal | vauthors = Bagri A, Kouros-Mehr H, Leong KG, Plowman GD | title = Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale | journal = Trends in Molecular Medicine | volume = 16 | issue = 3 | pages = 122–132 | date = March 2010 | pmid = 20189876 | doi = 10.1016/j.molmed.2010.01.004 }} [131] => [132] => ===Formation of tumor blood vessels=== [133] => The mechanism of blood vessel formation by angiogenesis is initiated by the spontaneous dividing of tumor cells due to a mutation. Angiogenic stimulators are then released by the tumor cells. These then travel to already established, nearby blood vessels and activates their endothelial cell receptors. This induces a release of [[proteolytic]] enzymes from the vasculature. These enzymes target a particular point on the blood vessel and cause a pore to form. This is the point where the new blood vessel will grow from. The reason tumour cells need a blood supply is because they cannot grow any more than 2-3 millimeters in diameter without an established blood supply which is equivalent to about 50-100 cells.{{cite journal | vauthors = Nishida N, Yano H, Nishida T, Kamura T, Kojiro M | title = Angiogenesis in cancer | journal = Vascular Health and Risk Management | volume = 2 | issue = 3 | pages = 213–219 | date = September 2006 | pmid = 17326328 | pmc = 1993983 | doi = 10.2147/vhrm.2006.2.3.213 | doi-access = free }} Certain studies have indicated that vessels formed inside the tumor tissue are of higher irregularity and bigger in size, which is as well associated with poorer prognosis.{{cite journal | vauthors = Milosevic V, Edelmann RJ, Winge I, Strell C, Mezheyeuski A, Knutsvik G, Askeland C, Wik E, Akslen LA, Östman A | display-authors = 6 | title = Vessel size as a marker of survival in estrogen receptor positive breast cancer | journal = Breast Cancer Research and Treatment | volume = 200 | issue = 2 | pages = 293–304 | date = July 2023 | pmid = 37222874 | pmc = 10241708 | doi = 10.1007/s10549-023-06974-4 }}{{cite journal | vauthors = Mikalsen LT, Dhakal HP, Bruland ØS, Naume B, Borgen E, Nesland JM, Olsen DR | title = The clinical impact of mean vessel size and solidity in breast carcinoma patients | journal = PLOS ONE | volume = 8 | issue = 10 | pages = e75954 | date = 2013-10-11 | pmid = 24146798 | pmc = 3795733 | doi = 10.1371/journal.pone.0075954 | bibcode = 2013PLoSO...875954M | doi-access = free | veditors = Aoki I }} [134] => [135] => ===Angiogenesis for cardiovascular disease=== [136] => Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely ''neoangiogenesis'': the production of new collateral vessels to overcome the ischemic insult. A large number of preclinical studies have been performed with protein-, gene- and cell-based therapies in animal models of cardiac ischemia, as well as models of peripheral artery disease. Reproducible and credible successes in these early animal studies led to high enthusiasm that this new therapeutic approach could be rapidly translated to a clinical benefit for millions of patients in the Western world with these disorders. A decade of clinical testing both gene- and protein-based therapies designed to stimulate angiogenesis in underperfused tissues and organs, however, has led from one disappointment to another. Although all of these preclinical readouts, which offered great promise for the transition of angiogenesis therapy from animals to humans, were in one fashion or another, incorporated into early stage clinical trials, the FDA has, to date (2007), insisted that the primary endpoint for approval of an angiogenic agent must be an improvement in exercise performance of treated patients.{{cite journal | vauthors = Hariawala MD, Sellke FW | title = Angiogenesis and the heart: therapeutic implications | journal = Journal of the Royal Society of Medicine | volume = 90 | issue = 6 | pages = 307–311 | date = June 1997 | pmid = 9227376 | pmc = 1296305 | doi = 10.1177/014107689709000604 }} [137] => [138] => These failures suggested that either these are the wrong molecular targets to induce neovascularization, that they can only be effectively used if formulated and administered correctly, or that their [[presentation (medical)|presentation]] in the context of the overall cellular microenvironment may play a vital role in their utility. It may be necessary to present these proteins in a way that mimics natural signaling events, including the [[concentration]], [[space|spatial]] and [[Time|temporal]] profiles, and their simultaneous or sequential presentation with other appropriate factors.{{cite journal | vauthors = Cao L, Mooney DJ | title = Spatiotemporal control over growth factor signaling for therapeutic neovascularization | journal = Advanced Drug Delivery Reviews | volume = 59 | issue = 13 | pages = 1340–1350 | date = November 2007 | pmid = 17868951 | pmc = 2581871 | doi = 10.1016/j.addr.2007.08.012 }} [139] => [140] => ===Exercise=== [141] => Angiogenesis is generally associated with [[aerobic exercise]] and [[endurance exercise]]. While [[arteriogenesis]] produces network changes that allow for a large increase in the amount of total flow in a network, angiogenesis causes changes that allow for greater nutrient delivery over a long period of time. Capillaries are designed to provide maximum nutrient delivery efficiency, so an increase in the number of capillaries allows the network to deliver more nutrients in the same amount of time. A greater number of capillaries also allows for greater oxygen exchange in the network. This is vitally important to endurance training, because it allows a person to continue training for an extended period of time. However, no experimental evidence suggests that increased capillarity is required in endurance exercise to increase the maximum oxygen delivery. [142] => [143] => ===Macular degeneration=== [144] => Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet [[macular degeneration]], VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes [[edema]], blood and other retinal fluids leak into the [[retina]], causing loss of vision. Anti-angiogenic drugs targeting the VEGF pathways are now used successfully to treat this type of macular degeneration [145] => [146] => ===Tissue engineered constructs=== [147] => Angiogenesis of vessels from the host body into an implanted tissue engineered constructs is essential. Successful integration is often dependent on thorough vascularisation of the construct as it provides oxygen and nutrients and prevents necrosis in the central areas of the implant.{{cite journal | vauthors = Rouwkema J, Khademhosseini A | title = Vascularization and Angiogenesis in Tissue Engineering: Beyond Creating Static Networks | journal = Trends in Biotechnology | volume = 34 | issue = 9 | pages = 733–745 | date = September 2016 | pmid = 27032730 | doi = 10.1016/j.tibtech.2016.03.002 | url = https://research.utwente.nl/en/publications/f67df178-6066-4fe2-afb3-58a570fe4b78 }} PDGF has been shown to stabilize vascularisation in collagen-glycosaminoglycan scaffolds.{{cite journal | vauthors = do Amaral RJ, Cavanagh B, O'Brien FJ, Kearney CJ | title = Platelet-derived growth factor stabilises vascularisation in collagen-glycosaminoglycan scaffolds in vitro | journal = Journal of Tissue Engineering and Regenerative Medicine | volume = 13 | issue = 2 | pages = 261–273 | date = February 2019 | pmid = 30554484 | doi = 10.1002/term.2789 | s2cid = 58767660 | doi-access = free }} [148] => [149] => ==History== [150] => The first report of angiogenesis can be traced back to the book ''A treatise on the blood, inflammation, and gun-shot wounds'' published in 1794, where Scottish anatomist [[John Hunter (surgeon)|John Hunter]]'s research findings were compiled. In his study, Hunter observed the growth process of new blood vessels in rabbits. However, he did not coin the term "Angiogenesis," which is now widely used by scholars. Hunter also erroneously attributed the growth process of new blood vessels to the effect of an innate vital principle within the blood. The term "angiogenesis" is believed to have emerged not until the 1900s. The inception of modern angiogenesis research is marked by Judah Folkman's report on the pivotal role of angiogenesis in tumor growth.{{cite journal | vauthors = Lenzi P, Bocci G, Natale G | title = John Hunter and the origin of the term "angiogenesis" | journal = Angiogenesis | volume = 19 | issue = 2 | pages = 255–256 | date = April 2016 | pmid = 26842740 | doi = 10.1007/s10456-016-9496-7 | publisher = Springer Science and Business Media LLC | s2cid = 254189385 | hdl = 11568/795270 | hdl-access = free }}{{cite book | vauthors = Adair TH, Montani JP | chapter = History | title=Angiogenesis | publisher=Morgan & Claypool Life Sciences | date=2010 | doi=10.4199/C00017ED1V01Y201009ISP009 | doi-broken-date=31 January 2024 | pmid=21452444 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK53238/#s1.1 | access-date=2023-07-20}} [151] => [152] => ==Quantification== [153] => Quantifying vasculature parameters such as microvascular density has various complications due to preferential staining or limited representation of tissues by histological sections. Recent research has shown complete 3D reconstruction of tumor vascular structure and quantification of vessel structures in whole tumors in animal models.{{cite journal | vauthors = Chien CC, Kempson IM, Wang CL, Chen HH, Hwu Y, Chen NY, Lee TK, Tsai KK, Liu MS, Chang KY, Yang CS, Margaritondo G | display-authors = 6 | title = Complete microscale profiling of tumor microangiogenesis: a microradiological methodology reveals fundamental aspects of tumor angiogenesis and yields an array of quantitative parameters for its characterization | journal = Biotechnology Advances | volume = 31 | issue = 3 | pages = 396–401 | date = May–June 2013 | pmid = 22193280 | doi = 10.1016/j.biotechadv.2011.12.001 }} [154] => [155] => == See also == [156] => {{col div|colwidth=18em}} [157] => *[[Aerobic exercise]] [158] => *[[Angiogenin]] [159] => *[[The Angiogenesis Foundation]] [160] => *[[Arteriogenesis]] [161] => *[[Collagen, type IV, alpha 1|COL41]] [162] => *[[Neuroangiogenesis]] [163] => *[[Proteases in angiogenesis]] [164] => *[[Vasculogenic mimicry]] [165] => {{colend}} [166] => [167] => == References == [168] => {{Reflist|32em}} [169] => [170] => == External links == [171] => *[http://www.ptca.org/angiogenesis/index.html Angiogenesis for Heart Disease from Angioplasty.Org] [172] => *[http://www.biochemweb.net/angiogenesis.shtml Angiogenesis - The Virtual Library of Biochemistry, Molecular Biology and Cell Biology] [173] => *[http://www.conncoll.edu/ccacad/zimmer/GFP-ww/cooluses1.html Visualizing Angiogenesis with GFP] [174] => *[http://www.nci.nih.gov/cancertopics/understandingcancer/angiogenesis/allpages NCI Understanding Cancer series on Angiogenesis] [175] => [176] => {{Wound healing}} [177] => {{Development of circulatory system}} [178] => {{Authority control}} [179] => [180] => [[Category:Angiogenesis]] [] => )
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Angiogenesis

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role.

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