713:(basic FGF) consists to date of at least 22 known members. 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. 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
1111:: 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.
865:. 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. 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.
1021:
1201:'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.
94:
1152:
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.
732:); 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.
1052:
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
1012:
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.
49:
1151:
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
1097:
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
760:
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
1056:. 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
943:
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
3859:
Chien CC, Kempson IM, Wang CL, Chen HH, Hwu Y, Chen NY, et al. (MayβJune 2013). "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".
1180:
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. PDGF has
955:
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, which require an
1011:
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,
1051:
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. Other clinicians believe angiogenesis really serves as a waste pathway, taking
765:
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
362:
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. Coalescent angiogenesis has extended out of the domain of embryology. It is assumed to play a
1209:
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
1092:
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
755:
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. VEGF causes a massive signaling cascade in
196:
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
1106:
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
2318:
Goto F, Goto K, Weindel K, Folkman J (November 1993). "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".
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established blood supply which is equivalent to about 50-100 cells. 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.
994:
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,
201:
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
766:
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.
332:
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
751:, although the results were more pronounced with VEGF. 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.
1003:
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
948:, 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
728:) 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 (
4034:
1071:
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
1118:
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
1531:
Arrabi N, Torabi M, Fassihi A, Ghasemi F (2024). "Identification of potential vascular endothelial growth factor receptor inhibitors via tree-based learning modeling and molecular docking simulation".
1114:
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
2571:
Haas TL, Milkiewicz M, Davis SJ, Zhou AL, Egginton S, Brown MD, et al. (October 2000). "Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle".
380:
acting on capillaries to cause angiogenesis, although current knowledge suggests that increased muscle contractions may increase angiogenesis. This may be due to an increase in the production of
4027:
3194:
McDougall SR, Anderson AR, Chaplain MA (August 2006). "Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies".
2673:
HellstrΓΆm M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. (February 2007). "Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis".
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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
1036:. 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 1β2 mm).
4020:
2875:"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"
968:. 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.
2407:
Gavin TP, Robinson CB, Yeager RC, England JA, Nifong LW, Hickner RC (January 2004). "Angiogenic growth factor response to acute systemic exercise in human skeletal muscle".
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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
1008:, 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.
1598:
Milosevic V, Edelmann RJ, Fosse JH, Γstman A, Akslen LA (2022). "Molecular
Phenotypes of Endothelial Cells in Malignant Tumors". In Akslen LA, Watnick RS (eds.).
261:
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
939:
characterized by either poor vascularisation or abnormal vasculature. Application of specific compounds that may inhibit or induce the creation of new
1558:
Torabi M, Yasami-Khiabani S, Sardari S, Ghasemi F (2024). "Identification of new potential candidates to inhibit EGF via machine learning algorithm".
1667:
Adair TH, Montani JP. Angiogenesis. San Rafael (CA): Morgan & Claypool Life
Sciences; 2010. Chapter 1, Overview of Angiogenesis. Available from:
3145:"The Application of Artificial Intelligence and Drug Repositioning for the Identification of Fibroblast Growth Factor Receptor Inhibitors: A Review"
488:
2493:
Lloyd PG, Prior BM, Yang HT, Terjung RL (May 2003). "Angiogenic growth factor expression in rat skeletal muscle in response to exercise training".
4176:
3939:
2450:
Kraus RM, Stallings HW, Yeager RC, Gavin TP (April 2004). "Circulating plasma VEGF response to exercise in sedentary and endurance-trained men".
1172:, causing loss of vision. Anti-angiogenic drugs targeting the VEGF pathways are now used successfully to treat this type of macular degeneration
1060:
and tumor cells. This mosaicity allows for substantial shedding of tumor cells into the vasculature, possibly contributing to the appearance of
3307:
1645:
1615:
1287:
2283:
Khurana R, Simons M (April 2003). "Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease".
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in the peripheral blood of patients with malignancies. The subsequent growth of such metastases will also require a supply of nutrients and
3332:"Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases"
1020:
242:
and form solid sprouts connecting neighboring vessels. The cells that are proliferating are located behind the tip cells and are known as
743:(VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network. Initial
896:
receptor binding at endothelial cells. The relative expression levels of SEMA3s and VEGF-A may therefore be important for angiogenesis.
747:
studies demonstrated bovine capillary endothelial cells will proliferate and show signs of tube structures upon stimulation by VEGF and
1501:
265:. It is markedly different from splitting angiogenesis because it forms entirely new vessels as opposed to splitting existing vessels.
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1040:
988:
740:
718:
425:
392:
Chemical stimulation of angiogenesis is performed by various angiogenic proteins e.g. integrins and prostaglandins, including several
3371:
Bagri A, Kouros-Mehr H, Leong KG, Plowman GD (March 2010). "Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale".
616:
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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
4108:
2826:"Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor"
480:
376:
Mechanical stimulation of angiogenesis is not well characterized. There is a significant amount of controversy with regard to
729:
463:
2528:
Thurston G (October 2003). "Role of
Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis".
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to escape into the interstitial matrix as seen in sprouting angiogenesis. Inhibition of MMPs prevents the formation of new
2393:
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279:
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4143:
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Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet
980:
140:
form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during
2775:"Simultaneous blockade of VEGF and Dll4 by HD105, a bispecific antibody, inhibits tumor progression and angiogenesis"
2198:
Blaber M, DiSalvo J, Thomas KA (February 1996). "X-ray crystal structure of human acidic fibroblast growth factor".
3664:
1488:
Flamme I, FrΓΆlich T, Risau W (November 1997). "Molecular mechanisms of vasculogenesis and embryonic angiogenesis".
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862:
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861:(Dll4) is a protein with a negative regulatory effect on angiogenesis. Dll4 is a transmembrane ligand, for the
827:
702:
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136:, although discussions are not always precise (especially in older texts). The first vessels in the developing
64:
2348:"Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke"
4238:
4171:
3704:"Platelet-derived growth factor stabilises vascularisation in collagen-glycosaminoglycan scaffolds in vitro"
961:
359:
354:
207:
117:
1164:, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes
341:. This is especially important in embryonic development as there are not enough resources to create a rich
4233:
4123:
3925:
2207:
1115:
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911:
905:
676:
Modulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeability
164:
93:
76:
952:, may be created by a local expansion of blood vessels, interfering with normal physiological processes.
4408:
4243:
4153:
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Mikalsen LT, Dhakal HP, Bruland ΓS, Naume B, Borgen E, Nesland JM, Olsen DR (2013-10-11). Aoki I (ed.).
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1198:
626:
602:
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Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts
2724:
Segarra M, Williams CK, Sierra Mde L, Bernardo M, McCormick PJ, Maric D, et al. (September 2008).
3059:
Stegmann TJ, Hoppert T, Schneider A, Gemeinhardt S, KΓΆcher M, Ibing R, Strupp G (September 2000). "".
2614:
Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ (February 2007).
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2682:
2627:
2101:
2042:
1255:
1161:
949:
847:
663:
608:
494:
329:
2212:
2090:"Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke"
175:, who described tumors as "hot and bloody," illustrating that, at least for many tumor types, flush
4079:
1888:
Prior BM, Yang HT, Terjung RL (September 2004). "What makes vessels grow with exercise training?".
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585:
3751:
Lenzi P, Bocci G, Natale G (April 2016). "John Hunter and the origin of the term "angiogenesis"".
778:, Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse
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4351:
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4069:
4044:
3969:
3839:
3786:
3733:
3457:
Milosevic V, Edelmann RJ, Winge I, Strell C, Mezheyeuski A, Knutsvik G, et al. (July 2023).
3250:
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1861:
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consists of a population of rapidly dividing and growing cancer cells that progressively accrues
473:
246:. The proliferation of these cells allows the capillary sprout to grow in length simultaneously.
152:
133:
113:
2616:"Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting"
214:
present in pre-existing blood vessels. Second, the activated endothelial cells, also known as
4363:
4331:
4253:
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3877:
3821:
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3725:
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3645:
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2225:
2180:
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2070:
2011:
1980:"A perspective on the role of class III semaphorin signaling in central nervous system trauma"
1955:
1905:
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1611:
1575:
1505:
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and nutrients to proliferate, pro-angiogenic therapies are being explored as options to treat
877:
227:
198:
1781:
Nitzsche B, Rong WW, Goede A, Hoffmann B, Scarpa F, Kuebler WM, et al. (February 2022).
1404:
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798:; while this is somewhat controversial, it seems that cell signals are transmitted mostly by
249:
As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in
4371:
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4084:
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3813:
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3715:
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3470:
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2001:
1991:
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profiles, and their simultaneous or sequential presentation with other appropriate factors.
1039:
Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g.
919:
835:
807:
342:
338:
239:
231:
211:
2088:
Rust R, Weber RZ, GrΓΆnnert L, Mulders G, Maurer MA, Hofer AS, et al. (December 2019).
2031:"Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke"
724:
Besides FGF-1, one of the most important functions of fibroblast growth factor-2 (FGF-2 or
639:
4382:
4148:
1077:
1029:
815:
294:
258:
3665:"Vascularization and Angiogenesis in Tissue Engineering: Beyond Creating Static Networks"
1028:
Cancer cells are cells that have lost their ability to divide in a controlled fashion. A
991:, VEGF; and cell-based therapies, which involve the implantation of specific cell types.
286:, is the formation of a new blood vessel by splitting an existing blood vessel into two.
4012:
3616:"Spatiotemporal control over growth factor signaling for therapeutic neovascularization"
3523:
3483:
3458:
3207:
3171:
3144:
3029:
2986:
2935:
2726:"Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth"
2686:
2631:
2105:
2046:
1734:"Intussusceptive angiogenesis: its emergence, its characteristics, and its significance"
1466:
1332:
1307:
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Regulates endothelial cell migration and proliferation. Alters vascular permeability.
4402:
4301:
4210:
4133:
4089:
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4061:
3974:
3948:
3873:
3790:
1865:
1783:"Coalescent angiogenesis-evidence for a novel concept of vascular network maturation"
1406:"Coalescent angiogenesis-evidence for a novel concept of vascular network maturation"
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965:
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779:
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121:
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are highly regulated during the vessel formation process because destruction of the
147:
Angiogenesis is a normal and vital process in growth and development, as well as in
69:
4205:
3508:"The clinical impact of mean vessel size and solidity in breast carcinoma patients"
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2710:
2600:
2557:
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Ding YH, Luan XD, Li J, Rafols JA, Guthinkonda M, Diaz FG, Ding Y (December 2004).
1073:
976:
512:
381:
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171:. The essential role of angiogenesis in tumor growth was first proposed in 1971 by
105:
3680:
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3331:
2859:
2791:
1355:
Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O (July 2014).
230:
to allow endothelial cells to escape from the original (parent) vessel walls. The
3532:
3459:"Vessel size as a marker of survival in estrogen receptor positive breast cancer"
3384:
3297:
2741:
1700:
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1000:
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298:
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125:
120:, vessel elongation and vessel cooption also play a role. Vasculogenesis is the
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Proceedings of the
National Academy of Sciences of the United States of America
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Proceedings of the
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Ferrara N, Kerbel RS (December 2005). "Angiogenesis as a therapeutic target".
2873:
Herzog B, Pellet-Many C, Britton G, Hartzoulakis B, Zachary IC (August 2011).
2541:
1225:
1053:
915:
893:
885:
873:
671:
657:
645:
568:
508:
309:
180:
3016:
Folkman J (September 1996). "Fighting cancer by attacking its blood supply".
2363:
1996:
830:(MMP). MMPs help degrade the proteins that keep the vessel walls solid. This
206:) which is a proangiogenic growth factor. These biological signals activate
3984:
3120:
3103:
2994:
2890:
2640:
2055:
1832:"On coalescent angiogenesis and the remarkable flexibility of blood vessels"
519:
293:
rats. In this type of vessel formation, the capillary wall extends into the
176:
160:
3881:
3825:
3782:
3729:
3688:
3649:
3551:
3492:
3443:
3392:
3357:
3282:
3223:
3180:
3161:
3080:
2951:
2908:
2810:
2759:
2702:
2659:
2592:
2549:
2514:
2471:
2428:
2371:
2304:
2269:
2184:
2133:
2074:
2015:
1959:
1909:
1857:
1816:
1759:
1718:
1579:
1439:
1390:
1341:
975:, pro-angiogenic methods can be differentiated into three main categories:
3600:
3129:
3045:
3002:
2851:
2332:
2229:
1509:
1502:
10.1002/(SICI)1097-4652(199711)173:2<206::AID-JCP22>3.0.CO;2-C
1474:
48:
4378:
4321:
4316:
3959:
2773:
Lee D, Kim D, Choi YB, Kang K, Sung ES, Ahn JH, et al. (July 2016).
1033:
945:
881:
484:
325:
317:
290:
254:
223:
129:
17:
3773:
2943:
2694:
384:
during exercise. Nitric oxide results in vasodilation of blood vessels.
4306:
3072:
1750:
1733:
1084:
are thought to be an ideal target for therapies directed against them.
305:
3720:
3703:
2321:
Laboratory
Investigation; A Journal of Technical Methods and Pathology
2221:
116:
mainly by processes of sprouting and splitting, but processes such as
82:
1941:
1544:
1169:
1065:
957:
889:
843:
592:
250:
219:
203:
168:
137:
27:
Blood vessel formation, when new vessels emerge from existing vessels
3237:
Spill F, Guerrero P, Alarcon T, Maini PK, Byrne HM (February 2015).
2824:
Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (March 1998).
888:
can interfere with VEGF-mediated angiogenesis since both SEMA3s and
880:
adhesion, migration, proliferation, survival and the recruitment of
3406:
Nishida N, Yano H, Nishida T, Kamura T, Kojiro M (September 2006).
4367:
4355:
3702:
do Amaral RJ, Cavanagh B, O'Brien FJ, Kearney CJ (February 2019).
3255:
1308:"Pathological angiogenesis: mechanisms and therapeutic strategies"
1165:
1124:
984:
803:
799:
795:
791:
710:
706:
630:
467:
439:
435:
156:
3302:(first ed.). Boca Raton: Taylor & Francis. p. 347.
1357:"Type-2 pericytes participate in normal and tumoral angiogenesis"
790:
are protein growth factors which act by binding their receptors,
721:(VEGF), which primarily drives the formation of new capillaries.
257:. These sprouts then form loops to become a full-fledged vessel
3979:
3917:
2573:
American
Journal of Physiology. Heart and Circulatory Physiology
2495:
American
Journal of Physiology. Heart and Circulatory Physiology
1193:
The first report of angiogenesis can be traced back to the book
1128:
1048:
1044:
858:
787:
783:
762:
748:
725:
579:
502:
453:
449:
4016:
3921:
1926:"Endothelial integrins and angiogenesis: not so simple anymore"
979:, targeting genes of interest for amplification or inhibition;
108:
form from pre-existing vessels, formed in the earlier stage of
1024:
Without angiogenesis a tumor cannot grow beyond a limited size
653:
155:. However, it is also a fundamental step in the transition of
2973:
Folkman J, Klagsbrun M (January 1987). "Angiogenic factors".
983:, which primarily manipulates angiogenic growth factors like
363:
role in the formation of neovasculature, such as in a tumor.
935:
Angiogenesis may be a target for combating diseases such as
715:
distinguishes FGF-1 from other pro-angiogenic growth factors
1602:. Cham: Springer International Publishing. pp. 31β52.
1076:
directed at cancer cells, which rapidly mutate and acquire
1195:
A treatise on the blood, inflammation, and gun-shot wounds
814:
when ligand binding causes a dimerization that initiates
3759:(2). Springer Science and Business Media LLC: 255β256.
3708:
Journal of Tissue
Engineering and Regenerative Medicine
3567:"Angiogenesis and the heart: therapeutic implications"
850:
would decrease the integrity of the microvasculature.
3239:"Mesoscopic and continuum modelling of angiogenesis"
1181:
been shown to stabilize vascularisation in collagen-
802:; though some papers show physiologic signaling via
4330:
4290:
4270:
4252:
4224:
4196:
4189:
4164:
4098:
4060:
4051:
3898:
Angiogenesis for Heart Disease from Angioplasty.Org
63:
58:
41:
337:without a corresponding increase in the number of
3844:: CS1 maint: DOI inactive as of September 2024 (
1973:
1971:
1969:
1732:Burri PH, Hlushchuk R, Djonov V (November 2004).
345:with new cells every time a new vessel develops.
1978:Mecollari V, Nieuwenhuis B, Verhaagen J (2014).
1685:"Tip cells: master regulators of tubulogenesis?"
1593:
1591:
1589:
1280:Angiogenesis insights from a systematic overview
3913:NCI Understanding Cancer series on Angiogenesis
3663:Rouwkema J, Khademhosseini A (September 2016).
2382:. Archived from the original on April 19, 2012.
1455:Annual Review of Cell and Developmental Biology
1361:American Journal of Physiology. Cell Physiology
1273:
1271:
1168:, blood and other retinal fluids leak into the
944:essential functions. Several diseases, such as
104:is the physiological process through which new
97:3D medical animation still showing angiogenesis
4028:
3933:
1301:
1299:
1210:structures in whole tumors in animal models.
876:(SEMA3s) regulate angiogenesis by modulating
826:Another major contributor to angiogenesis is
8:
1883:
1881:
1879:
1877:
1875:
1689:Seminars in Cell & Developmental Biology
1669:https://www.ncbi.nlm.nih.gov/books/NBK53238/
1453:Risau W, Flamme I (1995). "Vasculogenesis".
1197:published in 1794, where Scottish anatomist
2243:
2241:
2239:
1629:
1627:
112:. Angiogenesis continues the growth of the
4193:
4057:
4035:
4021:
4013:
3940:
3926:
3918:
1678:
1676:
1139:Angiogenesis is generally associated with
914:can be endogenous or come from outside as
47:
3772:
3719:
3639:
3590:
3541:
3531:
3482:
3433:
3423:
3347:
3272:
3254:
3170:
3160:
3119:
2898:
2841:
2800:
2790:
2749:
2649:
2639:
2211:
2174:
2164:
2123:
2113:
2064:
2054:
2005:
1995:
1949:
1847:
1806:
1749:
1708:
1429:
1380:
1331:
597:Determine formation of arteries or veins
3571:Journal of the Royal Society of Medicine
1600:Biomarkers of the Tumor Microenvironment
1019:
705:(FGF) family with its prototype members
611:, releases and activates growth factors
403:
92:
4177:Protein signalling in heart development
3812:. Morgan & Claypool Life Sciences.
3104:"Angiogenic therapy of the human heart"
2250:Expert Opinion on Investigational Drugs
1830:Pezzella F, Kerbel RS (February 2022).
1306:Dudley AC, Griffioen AW (August 2023).
1267:
1102:Angiogenesis for cardiovascular disease
1043:) and proteins. Growth factors such as
964:, the number one cause of death in the
3837:
2385:
1922:Perhaps an inhibitor of angiogenesis:
289:Intussusception was first observed in
80:
38:
3565:Hariawala MD, Sellke FW (June 1997).
1930:The Journal of Clinical Investigation
1093:receptors. This induces a release of
53:Angiogenesis following vasculogenesis
7:
3463:Breast Cancer Research and Treatment
3296:Gonzalez-Perez RR, Rueda BR (2013).
931:Angiogenesis as a therapeutic target
3412:Vascular Health and Risk Management
1467:10.1146/annurev.cb.11.110195.000445
328:fibers into the core to provide an
4278:Vascular remodelling in the embryo
3614:Cao L, Mooney DJ (November 2007).
3038:10.1038/scientificamerican0996-150
1984:Frontiers in Cellular Neuroscience
1637:Retinal and Choroidal Angiogenesis
989:vascular endothelial growth factor
741:Vascular endothelial growth factor
719:vascular endothelial growth factor
253:, using adhesion molecules called
25:
3908:Visualizing Angiogenesis with GFP
3818:10.4199/C00017ED1V01Y201009ISP009
2585:10.1152/ajpheart.2000.279.4.H1540
2285:Trends in Cardiovascular Medicine
617:plasminogen activator inhibitor-1
4109:Primary interventricular foramen
3874:10.1016/j.biotechadv.2011.12.001
1683:Weavers H, Skaer H (July 2014).
1560:European Journal of Pharmacology
1088:Formation of tumor blood vessels
1080:to treatment. For this reason,
3243:Journal of Mathematical Biology
2464:10.1152/japplphysiol.01031.2003
2421:10.1152/japplphysiol.00748.2003
2166:10.1186/gb-2001-2-3-reviews3005
1902:10.1152/japplphysiol.00035.2004
304:are reorganized and the vessel
3620:Advanced Drug Delivery Reviews
3196:Journal of Theoretical Biology
2352:Current Neurovascular Research
1490:Journal of Cellular Physiology
1068:and a waste disposal pathway.
999:, inflammatory responses, and
806:as well. These receptors are
730:platelet-derived growth factor
1:
3804:Adair TH, Montani JP (2010).
3681:10.1016/j.tibtech.2016.03.002
3349:10.1158/1078-0432.CCR-04-0378
3299:Tumor angiogenesis regulators
2879:Molecular Biology of the Cell
2843:10.1016/s0092-8674(00)81402-6
2792:10.1080/19420862.2016.1171432
2452:Journal of Applied Physiology
2409:Journal of Applied Physiology
2297:10.1016/S1050-1738(02)00259-1
1890:Journal of Applied Physiology
3533:10.1371/journal.pone.0075954
3385:10.1016/j.molmed.2010.01.004
3373:Trends in Molecular Medicine
3149:Advanced Biomedical Research
2742:10.1182/blood-2007-11-126045
1701:10.1016/j.semcdb.2014.04.009
1572:10.1016/j.ejphar.2023.176176
1176:Tissue engineered constructs
280:Intussusceptive angiogenesis
275:Intussusceptive angiogenesis
269:Intussusceptive angiogenesis
4144:Primary interatrial foramen
3143:Zarei P, Ghasemi F (2024).
3102:Folkman J (February 1998).
2507:10.1152/ajpheart.00743.2002
2149:"Fibroblast growth factors"
1924:Sheppard D (October 2002).
1640:. Springer. pp. 119β.
1608:10.1007/978-3-030-98950-7_3
1231:The Angiogenesis Foundation
981:protein replacement therapy
444:Integrate survival signals
324:. These cells begin laying
163:one, leading to the use of
4425:
3632:10.1016/j.addr.2007.08.012
3583:10.1177/014107689709000604
3475:10.1007/s10549-023-06974-4
3216:10.1016/j.jtbi.2005.12.022
2262:10.1517/13543784.7.12.2011
2147:Ornitz DM, Itoh N (2001).
2115:10.1038/s41598-019-56634-1
1849:10.1007/s10456-021-09825-2
1799:10.1007/s10456-021-09824-3
1422:10.1007/s10456-021-09824-3
1373:10.1152/ajpcell.00084.2014
1324:10.1007/s10456-023-09876-7
1282:. New York: Nova Science.
903:
810:. Thus, they can initiate
694:
621:stabilizes nearby vessels
352:
272:
132:cell precursors, and from
29:
3955:
3765:10.1007/s10456-016-9496-7
3425:10.2147/vhrm.2006.2.3.213
3265:10.1007/s00285-014-0771-1
2542:10.1007/s00441-003-0749-6
2392:: CS1 maint: unfit URL (
1634:Penn JS (11 March 2008).
1251:Proteases in angiogenesis
863:notch family of receptors
159:from a benign state to a
75:
46:
3408:"Angiogenesis in cancer"
3336:Clinical Cancer Research
2530:Cell and Tissue Research
2364:10.2174/1567202043361875
1997:10.3389/fncel.2014.00328
1278:Santulli G, ed. (2013).
828:matrix metalloproteinase
703:fibroblast growth factor
697:Fibroblast growth factor
151:and in the formation of
30:Not to be confused with
4239:Posterior cardinal vein
4172:Aorticopulmonary septum
3820:(inactive 2024-09-12).
3669:Trends in Biotechnology
3121:10.1161/01.CIR.97.7.628
2995:10.1126/science.2432664
2891:10.1091/mbc.E09-12-1061
2641:10.1073/pnas.0611206104
2056:10.1073/pnas.1905309116
1062:circulating tumor cells
962:cardiovascular diseases
946:ischemic chronic wounds
926:Application in medicine
360:Coalescent angiogenesis
355:Coalescent angiogenesis
349:Coalescent angiogenesis
165:angiogenesis inhibitors
118:coalescent angiogenesis
4234:Anterior cardinal vein
4124:Atrioventricular canal
3862:Biotechnology Advances
3162:10.4103/abr.abr_170_23
1738:Developmental Dynamics
1025:
912:angiogenesis inhibitor
906:Angiogenesis inhibitor
662:Regulates endothelial
603:plasminogen activators
372:Mechanical stimulation
284:splitting angiogenesis
192:Sprouting angiogenesis
98:
77:Anatomical terminology
4244:Common cardinal veins
1023:
695:Further information:
565:matrix macromolecules
430:Affects permeability
238:into the surrounding
96:
4114:Endocardial cushions
1256:Vasculogenic mimicry
1162:macular degeneration
1156:Macular degeneration
950:macular degeneration
848:extracellular matrix
664:transdifferentiation
609:extracellular matrix
586:junctional molecules
495:extracellular matrix
388:Chemical stimulation
330:extracellular matrix
183:are characteristic.
167:in the treatment of
4080:Primitive ventricle
4043:Development of the
3524:2013PLoSO...875954M
3208:2006JThBi.241..564M
3030:1996SciAm.275c.150F
3018:Scientific American
2987:1987Sci...235..442F
2944:10.1038/nature04483
2936:2005Natur.438..967F
2695:10.1038/nature05571
2687:2007Natur.445..776H
2632:2007PNAS..104.3219L
2106:2019NatSR...920040R
2047:2019PNAS..11614270R
2041:(28): 14270β14279.
1006:Alzheimer's disease
973:mechanism of action
900:Chemical inhibition
874:Class 3 semaphorins
869:Class 3 semaphorins
859:Delta-like ligand 4
474:smooth muscle cells
466:(BB-homodimer) and
218:, begin to release
4388:Vitelline arteries
4352:Inferior vena cava
4119:Septum intermedium
4070:Truncus arteriosus
4045:circulatory system
3970:Granulation tissue
3073:10.1007/PL00001972
2579:(4): H1540βH1547.
2501:(5): H1668βH1678.
2159:(3): REVIEWS3005.
2094:Scientific Reports
1751:10.1002/dvdy.20184
1145:endurance exercise
1026:
1016:Tumor angiogenesis
818:on key tyrosines.
458:Stabilize vessels
153:granulation tissue
134:neovascularization
99:
4396:
4395:
4364:Ductus arteriosus
4332:Fetal circulation
4286:
4285:
4185:
4184:
4105:Atrioventricular
4099:Chamber formation
4010:
4009:
3721:10.1002/term.2789
3626:(13): 1340β1350.
3342:(20): 6897β6904.
3309:978-1-4665-8097-8
3155:(15): 9759β9815.
2981:(4787): 442β447.
2930:(7070): 967β974.
2885:(15): 2766β2776.
2681:(7129): 776β780.
2256:(12): 2011β2015.
2222:10.1021/bi9521755
1647:978-1-4020-6779-2
1617:978-3-030-98950-7
1566:(15): 9759β9815.
1289:978-1-62618-114-4
1246:Neuroangiogenesis
1183:glycosaminoglycan
1082:endothelial cells
1058:endothelial cells
920:dietary component
836:endothelial cells
709:(acidic FGF) and
688:
687:
339:endothelial cells
232:endothelial cells
228:basement membrane
226:that degrade the
212:endothelial cells
91:
90:
86:
16:(Redirected from
4416:
4372:Umbilical artery
4360:Pulmonary artery
4312:Connecting stalk
4194:
4139:Foramen secundum
4085:Primitive atrium
4058:
4037:
4030:
4023:
4014:
3942:
3935:
3928:
3919:
3886:
3885:
3856:
3850:
3849:
3843:
3835:
3833:
3832:
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3795:
3794:
3776:
3748:
3742:
3741:
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3699:
3693:
3692:
3660:
3654:
3653:
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3605:
3604:
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3562:
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3555:
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3535:
3503:
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3486:
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3437:
3427:
3403:
3397:
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3368:
3362:
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3351:
3327:
3321:
3320:
3318:
3316:
3293:
3287:
3286:
3276:
3258:
3234:
3228:
3227:
3191:
3185:
3184:
3174:
3164:
3140:
3134:
3133:
3123:
3099:
3093:
3092:
3056:
3050:
3049:
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3007:
3006:
2970:
2964:
2963:
2919:
2913:
2912:
2902:
2870:
2864:
2863:
2845:
2821:
2815:
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2804:
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2770:
2764:
2763:
2753:
2721:
2715:
2714:
2670:
2664:
2663:
2653:
2643:
2626:(9): 3219β3224.
2611:
2605:
2604:
2568:
2562:
2561:
2525:
2519:
2518:
2490:
2484:
2483:
2458:(4): 1445β1450.
2447:
2441:
2440:
2404:
2398:
2397:
2391:
2383:
2343:
2337:
2336:
2315:
2309:
2308:
2280:
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2273:
2245:
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2233:
2215:
2206:(7): 2086β2094.
2195:
2189:
2188:
2178:
2168:
2144:
2138:
2137:
2127:
2117:
2085:
2079:
2078:
2068:
2058:
2026:
2020:
2019:
2009:
1999:
1975:
1964:
1963:
1953:
1942:10.1172/JCI16713
1920:
1914:
1913:
1896:(3): 1119β1128.
1885:
1870:
1869:
1851:
1827:
1821:
1820:
1810:
1778:
1772:
1771:
1753:
1729:
1723:
1722:
1712:
1680:
1671:
1665:
1659:
1658:
1656:
1654:
1631:
1622:
1621:
1595:
1584:
1583:
1555:
1549:
1548:
1545:10.1002/cem.3545
1528:
1522:
1521:
1485:
1479:
1478:
1450:
1444:
1443:
1433:
1401:
1395:
1394:
1384:
1352:
1346:
1345:
1335:
1303:
1294:
1293:
1275:
1221:Aerobic exercise
1141:aerobic exercise
878:endothelial cell
808:tyrosine kinases
648:differentiation
404:
396:e.g. VEGF, FGF.
343:microvasculature
282:, also known as
144:and in disease.
83:edit on Wikidata
51:
39:
21:
4424:
4423:
4419:
4418:
4417:
4415:
4414:
4413:
4399:
4398:
4397:
4392:
4383:Vitelline veins
4326:
4294:hemangiogenesis
4292:
4282:
4266:
4248:
4220:
4181:
4160:
4149:Septum secundum
4094:
4047:
4041:
4011:
4006:
3995:Intussusception
3951:
3946:
3894:
3889:
3858:
3857:
3853:
3836:
3830:
3828:
3803:
3802:
3798:
3750:
3749:
3745:
3701:
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3696:
3662:
3661:
3657:
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3608:
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3101:
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2967:
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2767:
2723:
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2718:
2672:
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2667:
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2608:
2570:
2569:
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2527:
2526:
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2405:
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2384:
2345:
2344:
2340:
2317:
2316:
2312:
2282:
2281:
2277:
2247:
2246:
2237:
2213:10.1.1.660.7607
2197:
2196:
2192:
2146:
2145:
2141:
2087:
2086:
2082:
2028:
2027:
2023:
1977:
1976:
1967:
1923:
1921:
1917:
1887:
1886:
1873:
1829:
1828:
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1780:
1779:
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1731:
1730:
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1674:
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1648:
1633:
1632:
1625:
1618:
1597:
1596:
1587:
1557:
1556:
1552:
1530:
1529:
1525:
1487:
1486:
1482:
1452:
1451:
1447:
1403:
1402:
1398:
1354:
1353:
1349:
1305:
1304:
1297:
1290:
1277:
1276:
1269:
1265:
1260:
1216:
1207:
1191:
1178:
1158:
1137:
1109:neoangiogenesis
1104:
1090:
1078:drug resistance
1030:malignant tumor
1018:
933:
928:
908:
902:
884:. Furthermore,
871:
856:
824:
816:phosphorylation
772:
738:
699:
693:
559:
555:
548:
544:
537:
533:
489:TGF-Ξ² receptors
402:
390:
374:
369:
357:
351:
277:
271:
194:
189:
87:
54:
35:
28:
23:
22:
15:
12:
11:
5:
4422:
4420:
4412:
4411:
4401:
4400:
4394:
4393:
4391:
4390:
4385:
4375:
4374:
4348:Ductus venosus
4344:Umbilical vein
4340:umbilical cord
4336:
4334:
4328:
4327:
4325:
4324:
4319:
4314:
4309:
4304:
4298:
4296:
4291:Extraembryonic
4288:
4287:
4284:
4283:
4281:
4280:
4274:
4272:
4268:
4267:
4265:
4264:
4258:
4256:
4250:
4249:
4247:
4246:
4241:
4236:
4230:
4228:
4222:
4221:
4219:
4218:
4213:
4208:
4202:
4200:
4191:
4187:
4186:
4183:
4182:
4180:
4179:
4174:
4168:
4166:
4162:
4161:
4159:
4158:
4157:
4156:
4151:
4146:
4141:
4136:
4128:
4127:
4126:
4121:
4116:
4111:
4102:
4100:
4096:
4095:
4093:
4092:
4087:
4082:
4077:
4072:
4066:
4064:
4055:
4049:
4048:
4042:
4040:
4039:
4032:
4025:
4017:
4008:
4007:
4005:
4004:
4002:Vasculogenesis
3999:
3998:
3997:
3987:
3982:
3977:
3972:
3967:
3965:Maggot therapy
3962:
3956:
3953:
3952:
3947:
3945:
3944:
3937:
3930:
3922:
3916:
3915:
3910:
3905:
3900:
3893:
3892:External links
3890:
3888:
3887:
3868:(3): 396β401.
3851:
3796:
3743:
3714:(2): 261β273.
3694:
3675:(9): 733β745.
3655:
3606:
3577:(6): 307β311.
3557:
3518:(10): e75954.
3498:
3469:(2): 293β304.
3449:
3418:(3): 213β219.
3398:
3379:(3): 122β132.
3363:
3322:
3308:
3288:
3249:(3): 485β532.
3229:
3202:(3): 564β589.
3186:
3135:
3114:(7): 628β629.
3094:
3067:(6): 589β599.
3051:
3024:(3): 150β154.
3008:
2965:
2914:
2865:
2836:(6): 735β745.
2816:
2785:(5): 892β904.
2765:
2736:(5): 1904β11.
2716:
2665:
2606:
2563:
2520:
2485:
2442:
2399:
2358:(5): 411β420.
2338:
2327:(5): 508β517.
2310:
2291:(3): 116β122.
2275:
2235:
2190:
2153:Genome Biology
2139:
2080:
2021:
1965:
1936:(7): 913β914.
1915:
1871:
1822:
1773:
1744:(3): 474β488.
1724:
1695:(100): 91β99.
1672:
1660:
1646:
1623:
1616:
1585:
1550:
1523:
1496:(2): 206β210.
1480:
1445:
1396:
1367:(1): C25βC38.
1347:
1318:(3): 313β347.
1295:
1288:
1266:
1264:
1261:
1259:
1258:
1253:
1248:
1243:
1238:
1236:Arteriogenesis
1233:
1228:
1223:
1217:
1215:
1212:
1206:
1205:Quantification
1203:
1190:
1187:
1177:
1174:
1157:
1154:
1149:arteriogenesis
1136:
1133:
1103:
1100:
1089:
1086:
1017:
1014:
997:immunogenicity
971:Regarding the
932:
929:
927:
924:
904:Main article:
901:
898:
870:
867:
855:
852:
823:
820:
812:cell signaling
771:
768:
737:
734:
692:
689:
686:
685:
682:
678:
677:
674:
667:
666:
660:
650:
649:
642:
636:
635:
633:
623:
622:
619:
613:
612:
605:
599:
598:
595:
589:
588:
582:
572:
571:
561:
557:
553:
546:
542:
535:
531:
525:
524:
522:
516:
515:
505:
499:
498:
491:
477:
476:
470:
460:
459:
456:
446:
445:
442:
432:
431:
428:
422:
421:
418:
412:
411:
408:
401:
398:
394:growth factors
389:
386:
373:
370:
368:
365:
353:Main article:
350:
347:
322:myofibroblasts
314:growth factors
302:cell junctions
273:Main article:
270:
267:
193:
190:
188:
185:
110:vasculogenesis
89:
88:
79:
73:
72:
67:
61:
60:
56:
55:
52:
44:
43:
32:vasculogenesis
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
4421:
4410:
4407:
4406:
4404:
4389:
4386:
4384:
4380:
4377:
4376:
4373:
4369:
4365:
4361:
4357:
4353:
4349:
4345:
4341:
4338:
4337:
4335:
4333:
4329:
4323:
4320:
4318:
4315:
4313:
4310:
4308:
4305:
4303:
4302:Blood islands
4300:
4299:
4297:
4295:
4289:
4279:
4276:
4275:
4273:
4269:
4263:
4260:
4259:
4257:
4255:
4254:Lymph vessels
4251:
4245:
4242:
4240:
4237:
4235:
4232:
4231:
4229:
4227:
4223:
4217:
4214:
4212:
4211:Aortic arches
4209:
4207:
4204:
4203:
4201:
4199:
4195:
4192:
4188:
4178:
4175:
4173:
4170:
4169:
4167:
4163:
4155:
4154:Foramen ovale
4152:
4150:
4147:
4145:
4142:
4140:
4137:
4135:
4134:Septum primum
4132:
4131:
4129:
4125:
4122:
4120:
4117:
4115:
4112:
4110:
4107:
4106:
4104:
4103:
4101:
4097:
4091:
4090:Sinus venosus
4088:
4086:
4083:
4081:
4078:
4076:
4075:Bulbus cordis
4073:
4071:
4068:
4067:
4065:
4063:
4062:Tubular heart
4059:
4056:
4054:
4050:
4046:
4038:
4033:
4031:
4026:
4024:
4019:
4018:
4015:
4003:
4000:
3996:
3993:
3992:
3991:
3988:
3986:
3983:
3981:
3978:
3976:
3975:Growth factor
3973:
3971:
3968:
3966:
3963:
3961:
3958:
3957:
3954:
3950:
3949:Wound healing
3943:
3938:
3936:
3931:
3929:
3924:
3923:
3920:
3914:
3911:
3909:
3906:
3904:
3901:
3899:
3896:
3895:
3891:
3883:
3879:
3875:
3871:
3867:
3863:
3855:
3852:
3847:
3841:
3827:
3823:
3819:
3815:
3811:
3807:
3800:
3797:
3792:
3788:
3784:
3780:
3775:
3770:
3766:
3762:
3758:
3754:
3747:
3744:
3739:
3735:
3731:
3727:
3722:
3717:
3713:
3709:
3705:
3698:
3695:
3690:
3686:
3682:
3678:
3674:
3670:
3666:
3659:
3656:
3651:
3647:
3642:
3637:
3633:
3629:
3625:
3621:
3617:
3610:
3607:
3602:
3598:
3593:
3588:
3584:
3580:
3576:
3572:
3568:
3561:
3558:
3553:
3549:
3544:
3539:
3534:
3529:
3525:
3521:
3517:
3513:
3509:
3502:
3499:
3494:
3490:
3485:
3480:
3476:
3472:
3468:
3464:
3460:
3453:
3450:
3445:
3441:
3436:
3431:
3426:
3421:
3417:
3413:
3409:
3402:
3399:
3394:
3390:
3386:
3382:
3378:
3374:
3367:
3364:
3359:
3355:
3350:
3345:
3341:
3337:
3333:
3326:
3323:
3311:
3305:
3301:
3300:
3292:
3289:
3284:
3280:
3275:
3270:
3266:
3262:
3257:
3252:
3248:
3244:
3240:
3233:
3230:
3225:
3221:
3217:
3213:
3209:
3205:
3201:
3197:
3190:
3187:
3182:
3178:
3173:
3168:
3163:
3158:
3154:
3150:
3146:
3139:
3136:
3131:
3127:
3122:
3117:
3113:
3109:
3105:
3098:
3095:
3090:
3086:
3082:
3078:
3074:
3070:
3066:
3063:(in German).
3062:
3055:
3052:
3047:
3043:
3039:
3035:
3031:
3027:
3023:
3019:
3012:
3009:
3004:
3000:
2996:
2992:
2988:
2984:
2980:
2976:
2969:
2966:
2961:
2957:
2953:
2949:
2945:
2941:
2937:
2933:
2929:
2925:
2918:
2915:
2910:
2906:
2901:
2896:
2892:
2888:
2884:
2880:
2876:
2869:
2866:
2861:
2857:
2853:
2849:
2844:
2839:
2835:
2831:
2827:
2820:
2817:
2812:
2808:
2803:
2798:
2793:
2788:
2784:
2780:
2776:
2769:
2766:
2761:
2757:
2752:
2747:
2743:
2739:
2735:
2731:
2727:
2720:
2717:
2712:
2708:
2704:
2700:
2696:
2692:
2688:
2684:
2680:
2676:
2669:
2666:
2661:
2657:
2652:
2647:
2642:
2637:
2633:
2629:
2625:
2621:
2617:
2610:
2607:
2602:
2598:
2594:
2590:
2586:
2582:
2578:
2574:
2567:
2564:
2559:
2555:
2551:
2547:
2543:
2539:
2535:
2531:
2524:
2521:
2516:
2512:
2508:
2504:
2500:
2496:
2489:
2486:
2481:
2477:
2473:
2469:
2465:
2461:
2457:
2453:
2446:
2443:
2438:
2434:
2430:
2426:
2422:
2418:
2414:
2410:
2403:
2400:
2395:
2389:
2381:
2377:
2373:
2369:
2365:
2361:
2357:
2353:
2349:
2342:
2339:
2334:
2330:
2326:
2322:
2314:
2311:
2306:
2302:
2298:
2294:
2290:
2286:
2279:
2276:
2271:
2267:
2263:
2259:
2255:
2251:
2244:
2242:
2240:
2236:
2231:
2227:
2223:
2219:
2214:
2209:
2205:
2201:
2194:
2191:
2186:
2182:
2177:
2172:
2167:
2162:
2158:
2154:
2150:
2143:
2140:
2135:
2131:
2126:
2121:
2116:
2111:
2107:
2103:
2099:
2095:
2091:
2084:
2081:
2076:
2072:
2067:
2062:
2057:
2052:
2048:
2044:
2040:
2036:
2032:
2025:
2022:
2017:
2013:
2008:
2003:
1998:
1993:
1989:
1985:
1981:
1974:
1972:
1970:
1966:
1961:
1957:
1952:
1947:
1943:
1939:
1935:
1931:
1927:
1919:
1916:
1911:
1907:
1903:
1899:
1895:
1891:
1884:
1882:
1880:
1878:
1876:
1872:
1867:
1863:
1859:
1855:
1850:
1845:
1841:
1837:
1833:
1826:
1823:
1818:
1814:
1809:
1804:
1800:
1796:
1792:
1788:
1784:
1777:
1774:
1769:
1765:
1761:
1757:
1752:
1747:
1743:
1739:
1735:
1728:
1725:
1720:
1716:
1711:
1706:
1702:
1698:
1694:
1690:
1686:
1679:
1677:
1673:
1670:
1664:
1661:
1649:
1643:
1639:
1638:
1630:
1628:
1624:
1619:
1613:
1609:
1605:
1601:
1594:
1592:
1590:
1586:
1581:
1577:
1573:
1569:
1565:
1561:
1554:
1551:
1546:
1542:
1538:
1534:
1527:
1524:
1519:
1515:
1511:
1507:
1503:
1499:
1495:
1491:
1484:
1481:
1476:
1472:
1468:
1464:
1460:
1456:
1449:
1446:
1441:
1437:
1432:
1427:
1423:
1419:
1415:
1411:
1407:
1400:
1397:
1392:
1388:
1383:
1378:
1374:
1370:
1366:
1362:
1358:
1351:
1348:
1343:
1339:
1334:
1329:
1325:
1321:
1317:
1313:
1309:
1302:
1300:
1296:
1291:
1285:
1281:
1274:
1272:
1268:
1262:
1257:
1254:
1252:
1249:
1247:
1244:
1242:
1239:
1237:
1234:
1232:
1229:
1227:
1224:
1222:
1219:
1218:
1213:
1211:
1204:
1202:
1200:
1196:
1188:
1186:
1184:
1175:
1173:
1171:
1167:
1163:
1155:
1153:
1150:
1146:
1142:
1134:
1132:
1130:
1126:
1122:
1121:concentration
1117:
1112:
1110:
1101:
1099:
1096:
1087:
1085:
1083:
1079:
1075:
1069:
1067:
1063:
1059:
1055:
1050:
1046:
1042:
1037:
1035:
1031:
1022:
1015:
1013:
1009:
1007:
1002:
998:
992:
990:
986:
982:
978:
974:
969:
967:
966:Western world
963:
959:
956:abundance of
953:
951:
947:
942:
941:blood vessels
938:
937:heart disease
930:
925:
923:
921:
917:
913:
907:
899:
897:
895:
891:
887:
883:
879:
875:
868:
866:
864:
860:
853:
851:
849:
845:
841:
837:
833:
829:
821:
819:
817:
813:
809:
805:
801:
797:
793:
789:
785:
781:
777:
776:angiopoietins
770:Angiopoietins
769:
767:
764:
759:
754:
750:
746:
742:
735:
733:
731:
727:
722:
720:
716:
712:
708:
704:
698:
690:
683:
680:
679:
675:
673:
669:
668:
665:
661:
659:
655:
652:
651:
647:
643:
641:
638:
637:
634:
632:
628:
625:
624:
620:
618:
615:
614:
610:
606:
604:
601:
600:
596:
594:
591:
590:
587:
583:
581:
577:
574:
573:
570:
566:
562:
560:
549:
538:
527:
526:
523:
521:
518:
517:
514:
510:
506:
504:
501:
500:
496:
492:
490:
486:
482:
479:
478:
475:
471:
469:
465:
462:
461:
457:
455:
451:
448:
447:
443:
441:
437:
434:
433:
429:
427:
424:
423:
419:
417:
414:
413:
409:
406:
405:
399:
397:
395:
387:
385:
383:
379:
371:
366:
364:
361:
356:
348:
346:
344:
340:
336:
331:
327:
323:
319:
315:
311:
307:
303:
300:
296:
292:
287:
285:
281:
276:
268:
266:
264:
260:
256:
252:
247:
245:
241:
237:
233:
229:
225:
221:
217:
213:
209:
205:
200:
191:
186:
184:
182:
178:
174:
173:Judah Folkman
170:
166:
162:
158:
154:
150:
149:wound healing
145:
143:
139:
135:
131:
127:
124:formation of
123:
119:
115:
111:
107:
106:blood vessels
103:
95:
84:
78:
74:
71:
68:
66:
62:
57:
50:
45:
40:
37:
33:
19:
4409:Angiogenesis
4206:Dorsal aorta
4197:
3990:Angiogenesis
3989:
3865:
3861:
3854:
3829:. Retrieved
3810:Angiogenesis
3809:
3799:
3774:11568/795270
3756:
3753:Angiogenesis
3752:
3746:
3711:
3707:
3697:
3672:
3668:
3658:
3623:
3619:
3609:
3574:
3570:
3560:
3515:
3511:
3501:
3466:
3462:
3452:
3415:
3411:
3401:
3376:
3372:
3366:
3339:
3335:
3325:
3313:. Retrieved
3298:
3291:
3246:
3242:
3232:
3199:
3195:
3189:
3152:
3148:
3138:
3111:
3107:
3097:
3064:
3060:
3054:
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