Editing Angiogenesis (section)

===Chemical stimulation===
Chemical stimulation of angiogenesis is performed by various angiogenic proteins e.g. integrins and prostaglandins, including several [[growth factor]]s e.g. VEGF, FGF.

====Overview====
{|class="wikitable"
|-
! Stimulator !! Mechanism
|-
| [[fibroblast growth factor|FGF]] || Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts
|-
| [[vascular endothelial growth factor|VEGF]] || Affects permeability
|-
| [[VEGFR]] and [[NRP-1]] || Integrate survival signals
|-
| [[Ang1]] and [[Ang2]] || Stabilize vessels
|-
| [[platelet derived growth factor|PDGF]] (BB-homodimer) and [[PDGFR]] || recruit [[smooth muscle cell]]s
|-
| [[transforming growth factor beta|TGF-β]], [[endoglin]] and [[transforming growth factor beta receptor|TGF-β receptor]]s || ↑[[extracellular matrix]] production
|-
| [[CCL2]] ||Recruits [[lymphocyte]]s to sites of [[inflammation]]
|-
| [[Histamine]] ||
|-
| Integrins [[alpha-v beta-3|α<sub>V</sub>β<sub>3</sub>]], [[alpha-v beta-5|α<sub>V</sub>β<sub>5</sub>]] (?<ref>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 }}</ref>) and [[alpha-5 beta-1|α<sub>5</sub>β<sub>1</sub>]] || Bind [[matrix macromolecules]] and [[proteinase]]s
|-
| [[VE-cadherin]] and [[CD31]] || endothelial [[junctional molecule]]s
|-
| [[ephrin]] || Determine formation of arteries or veins
|-
| [[plasminogen activator]]s || remodels [[extracellular matrix]], releases and activates growth factors
|-
| [[plasminogen activator inhibitor-1]] || stabilizes nearby vessels
|-
| [[nitric oxide synthase|eNOS]] and [[COX-2]] ||
|-
| [[AC133]] || regulates [[angioblast]] differentiation
|-
| [[ID1]]/[[ID3 (gene)|ID3]] || Regulates endothelial [[transdifferentiation]]
|-
|Class 3 [[semaphorin]]s
|Modulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeability<ref name="Mecollari_2014">{{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 }}</ref>
|-
|Nogo-A ||Regulates endothelial cell migration and proliferation.<ref>{{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 }}</ref> Alters vascular permeability.<ref>{{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 }}</ref>
|}

====FGF====
{{Further|Fibroblast growth factor}}

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.<ref>{{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 }}</ref> 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.
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.<ref>{{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 }}</ref> 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.<ref name="Stegmann"/><ref>{{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 }}</ref>

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.

====VEGF====
[[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.<ref name="Goto1993">{{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 }}</ref> 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.<ref name="Ding2004">{{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 = usurped | 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 | url-access = subscription }}</ref><ref name="Gavin2004">{{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 }}</ref><ref name="Kraus2004">{{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 }}</ref><ref name="Lloyd2003">{{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 }}</ref> ''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.<ref name="Prior2004" />
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.<ref name="Prior2004" />

====Angiopoietins====
The [[angiopoietins]], Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse [[Gene knockout|knock out]] studies.<ref name="Thurston2003">{{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 }}</ref> [[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.

====MMP====
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]].<ref name="Haas2000">{{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 }}</ref> These [[enzyme]]s are highly regulated during the vessel formation process because destruction of the [[extracellular matrix]] would decrease the integrity of the microvasculature.<ref name="Prior2004" />

====Dll4====
[[DLL4|Delta-like ligand 4]] (Dll4) is a protein with a negative regulatory effect on angiogenesis.<ref>{{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 }}</ref><ref>{{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 }}</ref> 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.<ref name="pmid18577711">{{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 }}</ref> 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.<ref>{{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 }}</ref>

==== Class 3 semaphorins ====
[[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.<ref name="Mecollari_2014" /> Furthermore, [[semaphorin]]s can interfere with VEGF-mediated angiogenesis since both SEMA3s and [[VEGF-A]] compete for [[neuropilin]] receptor binding at endothelial cells.<ref name="Soker_1998">{{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 }}</ref><ref name="Herzog_2011">{{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 }}</ref> The relative expression levels of SEMA3s and VEGF-A may therefore be important for angiogenesis.<ref name="Mecollari_2014" />