Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise (especially in older texts). The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.
Angiogenesis following vasculogenesis
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. The essential role of angiogenesis in tumor growth was first proposed in 1971 by Judah Folkman, who described tumors as "hot and bloody," illustrating that, at least for many tumor types, flush perfusion and even hyperemia are characteristic.
Sprouting angiogenesis was the first identified form of angiogenesis and because of this, it is much more understood than intussusceptive angiogenesis. It occurs in several well-characterized stages. The initial signal comes from tissue areas that are devoid of vasculature. The hypoxia that is noted in these areas causes the tissues to demand the presence of nutrients and oxygen that will allow the tissue to carry out metabolic activities. Because of this, parenchymal cells will secrete vascular endothelial growth factor (VEGF-A) which is a proangiogenic growth factor. These biological signals activate receptors on endothelial cells present in pre-existing blood vessels. Second, the activated endothelial cells, also known as tip cells, begin to release enzymes called proteases that degrade the basement membrane to allow endothelial cells to escape from the original (parent) vessel walls. The endothelial cells then proliferate into the surrounding matrix and form solid sprouts connecting neighboring vessels. The cells that are proliferating are located behind the tip cells and are known as stalk cells. The proliferation of these cells allows the capillary sprout to grow in length simultaneously.
As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in tandem, using adhesion molecules called integrins. These sprouts then form loops to become a full-fledged vessel lumen as cells migrate to the site of angiogenesis. Sprouting occurs at a rate of several millimeters per day, and enables new vessels to grow across gaps in the vasculature. It is markedly different from splitting angiogenesis because it forms entirely new vessels as opposed to splitting existing vessels.
Intussusceptive angiogenesis, also known as splitting angiogenesis, is the formation of a new blood vessel by splitting an existing blood vessel into two.
Intussusception was first observed in neonatal rats. In this type of vessel formation, the capillary wall extends into the lumen to split a single vessel in two. There are four phases of intussusceptive angiogenesis. First, the two opposing capillary walls establish a zone of contact. Second, the endothelial cell junctions are reorganized and the vessel bilayer is perforated to allow growth factors and cells to penetrate into the lumen. Third, a core is formed between the 2 new vessels at the zone of contact that is filled with pericytes and myofibroblasts. These cells begin laying collagen fibers into the core to provide an extracellular matrix for growth of the vessel lumen. Finally, the core is fleshed out with no alterations to the basic structure. Intussusception is important because it is a reorganization of existing cells. It allows a vast increase in the number of capillaries without a corresponding increase in the number of endothelial cells. This is especially important in embryonic development as there are not enough resources to create a rich microvasculature with new cells every time a new vessel develops.
Mechanical stimulation of angiogenesis is not well characterized. There is a significant amount of controversy with regard to shear stress acting on capillaries to cause angiogenesis, although current knowledge suggests that increased muscle contractions may increase angiogenesis. This may be due to an increase in the production of nitric oxide during exercise. Nitric oxide results in vasodilation of blood vessels.
Chemical stimulation of angiogenesis is performed by various angiogenic proteins e.g. integrins and prostaglandins, including several growth factors e.g. VEGF, FGF.
|FGF||Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts|
|VEGFR and NRP-1||Integrate survival signals|
|Ang1 and Ang2||Stabilize vessels|
|PDGF (BB-homodimer) and PDGFR||recruit smooth muscle cells|
|TGF-β, endoglin and TGF-β receptors||↑extracellular matrix production|
|CCL2||Recruits lymphocytes to sites of inflammation|
|Integrins αVβ3, αVβ5 (?) and α5β1||Bind matrix macromolecules and proteinases|
|VE-cadherin and CD31||endothelial junctional molecules|
|ephrin||Determine formation of arteries or veins|
|plasminogen activators||remodels extracellular matrix, releases and activates growth factors|
|plasminogen activator inhibitor-1||stabilizes nearby vessels|
|eNOS and COX-2|
|AC133||regulates angioblast differentiation|
|ID1/ID3||Regulates endothelial transdifferentiation|
|Class 3 semaphorins||Modulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeability|
|Nogo-A||Regulates endothelial cell migration and proliferation. Alters vascular permeability.|
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. 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 distinguishes FGF-1 from other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF), which primarily drives the formation of new capillaries.
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.
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. 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. 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. VEGF causes a massive signaling cascade in 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.
The angiopoietins, Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse knock out studies. 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.
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 cells to escape into the interstitial matrix as seen in sprouting angiogenesis. Inhibition of MMPs prevents the formation of new capillaries. These enzymes are highly regulated during the vessel formation process because destruction of the extracellular matrix would decrease the integrity of the microvasculature.
Delta-like ligand 4 (DII4) is a protein with a negative regulatory effect on angiogenesis. 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 DII4 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 DII4 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. 
Class 3 semaphorinsEdit
Class 3 semaphorins (SEMA3s) regulate angiogenesis by modulating endothelial cell adhesion, migration, proliferation, survival and the recruitment of pericytes. Furthermore, semaphorins can interfere with VEGF-mediated angiogenesis since both SEMA3s and VEGF-A compete for neuropilin receptor binding at endothelial cells. The relative expression levels of SEMA3s and VEGF-A may therefore be important for angiogenesis.
Application in medicineEdit
Angiogenesis as a therapeutic targetEdit
Angiogenesis may be a target for combating diseases such as heart disease characterized by either poor vascularisation or abnormal vasculature. 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 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, 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.
Also, 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.
In contrast, pro-angiogenic protein therapy uses well-defined, precisely structured proteins, with previously defined optimal doses of the individual protein for disease states, and with well-known biological effects. On the other hand, an obstacle of protein therapy is the mode of delivery. Oral, intravenous, intra-arterial, or intramuscular routes of protein administration are not always as effective, as the therapeutic protein may be metabolized or cleared before it can enter the target tissue. Cell-based pro-angiogenic therapies are still early stages of research, with many open questions regarding best cell types and dosages to use.
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 mutations. However, tumors need a dedicated blood supply to provide the oxygen and other essential nutrients they require in order to grow beyond a certain size (generally 1–2 mm3).
Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. 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. Other clinicians believe angiogenesis really serves as a waste pathway, taking away the biological end products secreted by rapidly dividing cancer cells. In either case, angiogenesis is a necessary and required step for transition from a small harmless cluster of cells, often said to be about the size of the metal ball at the end of a ball-point pen, to a large tumor. Angiogenesis is also required for the spread of a tumor, or metastasis. Single cancer cells can break away from an established solid tumor, enter the blood vessel, and be carried to a distant site, where they can implant and begin the growth of a secondary tumor. Evidence now suggests the blood vessel in a given solid tumor may, in fact, be mosaic vessels, composed of endothelial cells and tumor cells. This mosaicity allows for substantial shedding of tumor cells into the vasculature, possibly contributing to the appearance of circulating tumor cells in the peripheral blood of patients with malignancies. 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.
Formation of tumor blood vesselsEdit
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.
Angiogenesis for cardiovascular diseaseEdit
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 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 suffering from 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.
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 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, spatial and temporal profiles, and their simultaneous or sequential presentation with other appropriate factors.
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.
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 constructsEdit
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 been shown to stabilize vascularisation in collagen-glycosaminoglycan scaffolds.
Quantifying vasculature parameters such as microvascular density has various complications due to preferential staining or limited representation of tissues by histological sections. Recent research has shown complete 3D reconstruction of tumor vascular structure and quantification of vessel structures in whole tumors in animal models.
- Angiogenesis insights from a systematic overview. New York: Nova Science. 2013. ISBN 978-1-62618-114-4.
- Birbrair A, Zhang T, Wang ZM, Messi ML, Mintz A, Delbono O (January 2015). "Pericytes at the intersection between tissue regeneration and pathology". Clinical Science. 128 (2): 81–93. doi:10.1042/CS20140278. PMC 4200531. PMID 25236972.
- Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O (July 2014). "Type-2 pericytes participate in normal and tumoral angiogenesis". American Journal of Physiology. Cell Physiology. 307 (1): C25-38. doi:10.1152/ajpcell.00084.2014. PMC 4080181. PMID 24788248.
- "Lymphatic vasculature development" (PDF). www.columbia.edu. Retrieved 17 December 2018.
- Risau W, Flamme I (1995). "Vasculogenesis". Annual Review of Cell and Developmental Biology. 11: 73–91. doi:10.1146/annurev.cb.11.110195.000445. PMID 8689573.
- Flamme I, Frölich T, Risau W (November 1997). "Molecular mechanisms of vasculogenesis and embryonic angiogenesis". Journal of Cellular Physiology. 173 (2): 206–10. doi:10.1002/(SICI)1097-4652(199711)173:2<206::AID-JCP22>3.0.CO;2-C. PMID 9365523.
- John S. Penn (11 March 2008). Retinal and Choroidal Angiogenesis. Springer. pp. 119–. ISBN 978-1-4020-6779-2. Retrieved 26 June 2010.
- Adair TH, Montani JP. Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences; 2010. Chapter 1, Overview of Angiogenesis. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53238/
- Burri PH, Hlushchuk R, Djonov V (November 2004). "Intussusceptive angiogenesis: its emergence, its characteristics, and its significance". Developmental Dynamics. 231 (3): 474–88. doi:10.1002/dvdy.20184. PMID 15376313.
- Prior BM, Yang HT, Terjung RL (September 2004). "What makes vessels grow with exercise training?". Journal of Applied Physiology. 97 (3): 1119–28. doi:10.1152/japplphysiol.00035.2004. PMID 15333630.
- Perhaps an inhibitor of angiogenesis: Sheppard D (October 2002). "Endothelial integrins and angiogenesis: not so simple anymore". The Journal of Clinical Investigation. 110 (7): 913–4. doi:10.1172/JCI16713. PMC 151161. PMID 12370267.
- Mecollari V, Nieuwenhuis B, Verhaagen J (2014). "A perspective on the role of class III semaphorin signaling in central nervous system trauma". Frontiers in Cellular Neuroscience. 8: 328. doi:10.3389/fncel.2014.00328. PMC 4209881. PMID 25386118.
- Rust, Ruslan; Grönnert, Lisa; Gantner, Christina; Enzler, Alinda; Mulders, Geertje; Weber, Rebecca Z.; Siewert, Arthur; Limasale, Yanuar D. P.; Meinhardt, Andrea; Maurer, Michael A.; Sartori, Andrea M.; Hofer, Anna-Sophie; Werner, Carsten; Schwab, Martin E. (9 July 2019). "Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke". Proceedings of the National Academy of Sciences. 116 (28): 14270–14279. doi:10.1073/pnas.1905309116. PMC 6628809. PMID 31235580.
- Rust, Ruslan; Weber, Rebecca Z.; Grönnert, Lisa; Mulders, Geertje; Maurer, Michael A.; Hofer, Anna-Sophie; Sartori, Andrea M.; Schwab, Martin E. (27 December 2019). "Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke". Scientific Reports. 9 (1): 20040. doi:10.1038/s41598-019-56634-1. PMC 6934709. PMID 31882970.
- Ornitz DM, Itoh N (2001). "Fibroblast growth factors". Genome Biology. 2 (3): REVIEWS3005. doi:10.1186/gb-2001-2-3-reviews3005. PMC 138918. PMID 11276432.
- Blaber M, DiSalvo J, Thomas KA (February 1996). "X-ray crystal structure of human acidic fibroblast growth factor". Biochemistry. 35 (7): 2086–94. CiteSeerX 10.1.1.660.7607. doi:10.1021/bi9521755. PMID 8652550.
- Stegmann TJ (December 1998). "FGF-1: a human growth factor in the induction of neoangiogenesis". Expert Opinion on Investigational Drugs. 7 (12): 2011–5. doi:10.1517/135437184.108.40.2061. PMID 15991943.
- Khurana R, Simons M (April 2003). "Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease". Trends in Cardiovascular Medicine. 13 (3): 116–22. doi:10.1016/S1050-1738(02)00259-1. PMID 12691676.
- 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". Laboratory Investigation; A Journal of Technical Methods and Pathology. 69 (5): 508–17. PMID 8246443.
- Ding YH, Luan XD, Li J, Rafols JA, Guthinkonda M, Diaz FG, Ding Y (December 2004). "Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke". Current Neurovascular Research. 1 (5): 411–20. doi:10.2174/1567202043361875. PMID 16181089. Archived from the original on April 19, 2012.
- 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". Journal of Applied Physiology. 96 (1): 19–24. doi:10.1152/japplphysiol.00748.2003. PMID 12949011. S2CID 12750224.
- Kraus RM, Stallings HW, Yeager RC, Gavin TP (April 2004). "Circulating plasma VEGF response to exercise in sedentary and endurance-trained men". Journal of Applied Physiology. 96 (4): 1445–50. doi:10.1152/japplphysiol.01031.2003. PMID 14660505.
- Lloyd PG, Prior BM, Yang HT, Terjung RL (May 2003). "Angiogenic growth factor expression in rat skeletal muscle in response to exercise training". American Journal of Physiology. Heart and Circulatory Physiology. 284 (5): H1668-78. doi:10.1152/ajpheart.00743.2002. PMID 12543634.
- Thurston G (October 2003). "Role of Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis". Cell and Tissue Research. 314 (1): 61–8. doi:10.1007/s00441-003-0749-6. PMID 12915980.
- Haas TL, Milkiewicz M, Davis SJ, Zhou AL, Egginton S, Brown MD, Madri JA, Hudlicka O (October 2000). "Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle". American Journal of Physiology. Heart and Circulatory Physiology. 279 (4): H1540-7. doi:10.1152/ajpheart.2000.279.4.H1540. PMID 11009439. S2CID 2543076.
- Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ (February 2007). "Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting". Proceedings of the National Academy of Sciences of the United States of America. 104 (9): 3219–24. Bibcode:2007PNAS..104.3219L. doi:10.1073/pnas.0611206104. PMC 1805530. PMID 17296940.
- 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 (February 2007). "Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis". Nature. 445 (7129): 776–80. Bibcode:2007Natur.445..776H. doi:10.1038/nature05571. PMID 17259973.
- Segarra M, Williams CK, Sierra ML, Bernarndo M, McCormick PJ, Meric D, Regino C, Choyke P, Tosato G. 2008. Dll4 activation of Notch signaling reduces tumore vascularity and inhibits tumor growth. Blood Journal. 112(5): 1904-1911
- Lee D, Kim D, Bin Choi Y, Kang K, Sung ES, Ahn JH, Goo J, Yeom DH, Sook Jang H, Duk Moon K, Hoon Lee S, You WK (2016). "Simultaneous blockade of VEGF and Dll4 by HD105, a bispecific antibody, inhibits tumor progression and angiogenesis". mAbs. 8 (5): 892–904. doi:10.1080/19420862.2016.1171432. PMC 4968104. PMID 27049350.
- Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (March 1998). "Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor". Cell. 92 (6): 735–45. doi:10.1016/s0092-8674(00)81402-6. PMID 9529250.
- Herzog B, Pellet-Many C, Britton G, Hartzoulakis B, Zachary IC (August 2011). "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". Molecular Biology of the Cell. 22 (15): 2766–76. doi:10.1091/mbc.E09-12-1061. PMC 3145551. PMID 21653826.
- Ferrara N, Kerbel RS (December 2005). "Angiogenesis as a therapeutic target". Nature. 438 (7070): 967–74. Bibcode:2005Natur.438..967F. doi:10.1038/nature04483. PMID 16355214.
- Folkman J, Klagsbrun M (January 1987). "Angiogenic factors". Science. 235 (4787): 442–7. Bibcode:1987Sci...235..442F. doi:10.1126/science.2432664. PMID 2432664.
- Folkman J (September 1996). "Fighting cancer by attacking its blood supply". Scientific American. 275 (3): 150–4. Bibcode:1996SciAm.275c.150F. doi:10.1038/scientificamerican0996-150. PMID 8701285.
- Stegmann TJ, Hoppert T, Schneider A, Gemeinhardt S, Köcher M, Ibing R, Strupp G (September 2000). "[Induction of myocardial neoangiogenesis by human growth factors. A new therapeutic approach in coronary heart disease]". Herz (in German). 25 (6): 589–99. doi:10.1007/PL00001972. PMID 11076317.
- Folkman J (February 1998). "Angiogenic therapy of the human heart". Circulation. 97 (7): 628–9. doi:10.1161/01.CIR.97.7.628. PMID 9495294.
- McDougall SR, Anderson AR, Chaplain MA (August 2006). "Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies". Journal of Theoretical Biology. 241 (3): 564–89. doi:10.1016/j.jtbi.2005.12.022. PMID 16487543.
- Spill F, Guerrero P, Alarcon T, Maini PK, Byrne HM (February 2015). "Mesoscopic and continuum modelling of angiogenesis". Journal of Mathematical Biology. 70 (3): 485–532. arXiv:1401.5701. doi:10.1007/s00285-014-0771-1. PMC 5320864. PMID 24615007.
- Gonzalez-Perez RR, Rueda BR (2013). Tumor angiogenesis regulators (first ed.). Boca Raton: Taylor & Francis. p. 347. ISBN 978-1-4665-8097-8. Retrieved 2 October 2014.
- Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW (October 2004). "Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases". Clinical Cancer Research. 10 (20): 6897–904. doi:10.1158/1078-0432.CCR-04-0378. PMID 15501967.
- Bagri A, Kouros-Mehr H, Leong KG, Plowman GD (March 2010). "Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale". Trends in Molecular Medicine. 16 (3): 122–32. doi:10.1016/j.molmed.2010.01.004. PMID 20189876.
- Nishida N, Yano H, Nishida T, Kamura T, Kojiro M (September 2006). "Angiogenesis in cancer". Vascular Health and Risk Management. 2 (3): 213–9. doi:10.2147/vhrm.2006.2.3.213. PMC 1993983. PMID 17326328.
- Hariawala MD, Sellke FW (June 1997). "Angiogenesis and the heart: therapeutic implications". Journal of the Royal Society of Medicine. 90 (6): 307–11. doi:10.1177/014107689709000604. PMC 1296305. PMID 9227376.
- Cao L, Mooney DJ (November 2007). "Spatiotemporal control over growth factor signaling for therapeutic neovascularization". Advanced Drug Delivery Reviews. 59 (13): 1340–50. doi:10.1016/j.addr.2007.08.012. PMC 2581871. PMID 17868951.
- Rouwkema, Jeroen; Khademhosseini, Ali (September 2016). "Vascularization and Angiogenesis in Tissue Engineering: Beyond Creating Static Networks". Trends in Biotechnology. 34 (9): 733–745. doi:10.1016/j.tibtech.2016.03.002. PMID 27032730.
- Amaral, Ronaldo Jose Farias Correa; Cavanagh, Brenton; O'Brien, Fergal Joseph; Kearney, Cathal John (16 December 2018). "Platelet‐derived growth factor stabilises vascularisation in collagen‐glycosaminoglycan scaffolds". Journal of Tissue Engineering and Regenerative Medicine. 13 (2): 261–273. doi:10.1002/term.2789. PMID 30554484.
- Chia-Chi Chien; Ivan M. Kempson; Cheng Liang Wang; H. H. Chen; Yeukuang Hwua; N. Y. Chen; T. K. Lee; Kelvin K.-C. Tsai; Ming-Sheng Liu; Kwang-Yu Change; C. S. Yang; G. Margaritondo (May–June 2013). "Complete microscale profiling of tumor microangiogenesis". Biotechnology Advances. 31 (3): 396–401. doi:10.1016/j.biotechadv.2011.12.001. PMID 22193280.
- Angiogenesis for Heart Disease from Angioplasty.Org
- Angiogenesis - The Virtual Library of Biochemistry, Molecular Biology and Cell Biology
- Visualizing Angiogenesis with GFP
- NCI Understanding Cancer series on Angiogenesis
- Adair, TH; Montani, J-P (2010). Angiogenesis. San Rafael: Morgan & Claypool Life Sciences. PMID 21452444. A textbook on the topic freely available at NCBI.