Editing Angiogenesis (section)

==Application in medicine==

===Angiogenesis as a therapeutic target===
Angiogenesis may be a target for combating diseases such as [[heart disease]] characterized by either poor vascularisation or abnormal vasculature.<ref>{{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 }}</ref> 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.

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,<ref>{{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 }}</ref><ref>{{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 }}</ref> 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.<ref name="Stegmann">{{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 }}</ref><ref name="Schumacher">{{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 }}</ref><ref>{{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 }}</ref><ref>{{cite journal |last1=Zarei |first1=Parvin  |last2=Ghasemi |first2=Fahimeh |title=The Application of Artificial Intelligence and Drug Repositioning for the Identification of Fibroblast Growth Factor Receptor Inhibitors: A Review |journal=Advanced Biomedical Research|date=2024 |language=en |volume=13 |issue=15 |pages=9759–9815 |doi= 10.4103/abr.abr_170_23 |doi-access=free |pmid=38525398 |pmc=10958741 }}</ref>

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.

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}}

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.<ref name="Santulli_2013"/> 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.

===Tumor angiogenesis===
[[File:Diagram showing why cancer cells need their own blood supply.svg|270px|thumb| Without angiogenesis a tumor cannot grow beyond a limited size]]
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&nbsp;mm<sup>3</sup>).<ref name="pmid16487543">{{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 }}</ref><ref>{{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 }}</ref>

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.<ref name="Gonzalez-Perez">{{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}}</ref>  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]].<ref name="Milosevic_2022" /> 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.<ref name="Milosevic_2022" /> 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.<ref>{{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 }}</ref> The subsequent growth of such metastases will also require a supply of nutrients and [[oxygen]] and a waste disposal pathway.

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.<ref>{{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 }}</ref>

===Formation of tumor blood vessels===
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.<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref><ref>{{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 }}</ref>

===Angiogenesis for cardiovascular disease===
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.<ref name="Stegmann"/> 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.<ref>{{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 }}</ref>

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.<ref>{{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 }}</ref>

===Exercise===
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.<ref name="Prior2004" />

===Macular degeneration===
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

===Tissue engineered constructs===
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.<ref>{{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 }}</ref>  PDGF has been shown to stabilize vascularisation in collagen-[[glycosaminoglycan]] scaffolds.<ref>{{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 }}</ref>