The creation of new blood vessels is referred to as angiogenesis. Endothelial cells, which line the inside wall of blood arteries, migrate, proliferate, and differentiate during this process. Chemical cues in the body influence the process of angiogenesis. This study intends to highlight the expression of various angiogenic indicators throughout various diseases, the involvement of pro-angiogenic and anti-angiogenic factors during angiogenesis, and the use of angiogenic inhibitors during antiangiogenic therapy, particularly in cancer.

Angiogenesis; Angiogenesis Markers; Pro-angiogenic Factors; Anti-angiogenic Factors; Anti-angiogenic Therapy

Angiogenesis, or the formation of new blood vessels from pre-existing vessels that allow oxygen and nutrients to reach the body's tissues, is not only important during embryogenesis and wound healing, but it also plays a role in the pathogenesis of many diseases, including cancer, proliferative retinopathy, and chronic inflammatory conditions. Angiogenesis regulation is linked to disorders like rheumatoid arthritis, diabetes, atherosclerosis, and cancer. Angiogenesis is a tightly controlled process.

The sequence of events that leads to new vessel formation begins with endothelial cell activation by an angiogenic stimulus, which causes the basement membrane and extracellular matrix to breakdown; then, the endothelial cells migrate and divide, forming new vessels, which mature with basement membrane reconstruction as the final step in the sequence [1,13].

Angiogenesis inducers include members of the vascular endothelial growth factor (VEGF) family, angiopoietins, transforming growth factors, platelet-derived growth factor, thrombospondin-1 (TSP-1), tumor necrosis factor-alpha (TNFα), interleukins, and members of the fibroblast growth factor family.

Angiogenesis occurs when proangiogenic and antiangiogenic factors fall out of balance [47].

Classical and non-classical proangiogenic factors (PFs) that activate in tumors induce angiogenesis [57]. Proangiogenic factors (PF) are potential targets of antiangiogenic therapies (e.g., monoclonal antibodies). All PFs induce the overexpression of several signaling pathways that lead to the migration and proliferation of endothelial cells and pericytes contributing to tumor angiogenesis and survival of cancer cells [57].

Proangiogenic factors are classed as classical or non-classical angiogenic factors.

Cassical proangiogenic factors are Vascular endothelial growth factor (VEGF), Fibroblast growth factor-2 (FGF-2), Platelet-derived growth factor (PDGF), Platelet-Derived Endothelial Cell Growth Factor (PD-ECGF), Angiopoietins (Ang), Hepatocyte growth factor (HGF), Insulin-like growth factors (IGFs).

Non-classical proangiogenic factors are Stem cell factor (SCF)-It is a GF overexpressed in various inflammatory diseases, Tryptase. -Tryptase is a preformed active neutral serine protease that is abundantly stored in the MC secretory granules, Chymase.

The main proangiogenic factors include VEGF and members of the angiopoietin family. Alternative splicing produces a variety of VEGF isoforms. The proliferation and migration of endothelial cells, as well as an increase in blood artery permeability, are all impacts of VEGF. VEGF binds to the VEGFR-1 and VEGFR-2 tyrosine kinase receptors, which are mostly produced by endothelial cells. [20] The most potent pro-angiogenic protein is vascular endothelial growth factor-A. It causes endothelial cells to proliferate, sprout, and form tubes.

Tie-2 is the receptor for angiopoietins. [73] Angiopoietin-1 promotes the development and stabilization of newly created vasculature by working in tandem with VEGF. Angiopoietin-2 is thought to be a natural angiopoietin-1 antagonist that makes endothelial cells more sensitive to the effects of VEGF.

Angiogenesis is significantly influenced by inflammatory mediators. Proangiogenic agents, such as VEGF or angiopoietins, upregulate many pro-inflammatory pathways, resulting in leukocyte recruitment, infiltration, and inflammatory mediator release. [15] The interaction of inflammation and angiogenesis is demonstrated by the ability of VEGF to drive T cells towards a T helper 1 phenotype by increasing IFN- and lowering IL-10 production [60].

Thrombospondins (TSP), angiostatin, and endostatin are the most important anti-angiogenic factors. TSP-1, -2, -3, -4, and TSP-5/COMP are now part of the TSP family. They carry out a variety of tasks by binding to matrix proteins, plasma proteins, and cytokines [6,25,35,61].

Urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and metalloproteinases (MMPs) act as proangiogenic factors during basement membrane disintegration, whereas tissue inhibitors of metalloproteinases (TiMPs) and Plasminogen Activator Inhibitor (PAI) act as antiangiogenic factors. During endothelial cell migration, vascular endothelial growth factors (VEGF-A, VEGF-B, VEGF-C, VEGF-D) behave as proangiogenic factors, while thrombospondin and angiostatin act as antiangiogenic factors.  Platelet-derived growth factor (PDGF), platelet-derived endothelial cell growth factor (PDECGF), and fibroblast growth factor (FGF) all operate as proangiogenic agents during endothelial cell proliferation. Antiangiogenic factors such as endostatin and prolactin may be present. Proangiogenic factors such as angiopoietin 1, tumor growth factor (TGF-), epidermal growth factor (EGF), and angiogenin are involved in the formation of lumen-bearing cords. Antiangiogenic agents include interferons and angiopoietin 2 [57].

Angiogenesis inhibitors are distinct cancer-fighting drugs in that they impede the formation of blood vessels that support tumor growth rather than tumor cell growth [1].

Angiogenesis inhibitors disrupt blood vessel creation at various stages in a variety of ways Some are monoclonal antibodies that identify and bind to VEGF selectively. The VEGF receptor cannot be activated when VEGF is coupled to these medications. Other angiogenesis inhibitors bind to VEGF and/or its receptor, as well as other receptors on endothelial cell surfaces and other proteins in downstream signaling cascades and prevent them from acting. Some angiogenesis inhibitors are antiangiogenic immunomodulatory medicines (agents that stimulate or suppress the immune system) [1].

Angiogenesis inhibitors appear to be most effective when coupled with other medications in some malignancies. Angiogenesis inhibitors are given over a long period because they function by slowing or preventing tumor growth without destroying cancer cells [1].

Rheumatoid arthritis is an inflammatory and autoimmune illness. Uncontrolled cell division, an inflammatory condition, and the creation of new vessels are all features of RA, just as they are in cancer. The synovial membrane and tendons have an inflammatory infiltration, as well as synovial-membrane hyperplasia. The loss of function is caused by the destruction of cartilage and subchondral bone. The progression of chronic disease is aided by the proliferation of blood vessels. The synovial mass requires a considerable amount of nutrients and oxygen, and the enlarged vascular network allows inflammatory cells and pro-inflammatory cytokines easy access to the synovium. In addition to the growth in blood vessels, the location of blood vessels inside the synovium changes, resulting in hypoxic foci [13].

Hypoxia promoted by synovial proliferation, together with the release of pro-inflammatory factors, acts as a powerful proangiogenic stimulus. Hypoxia-inducible factor (HIF) is highly inducible by hypoxia and inflammatory mediators, promoting angiogenesis and contributing to the pathogenesis of RA. [27] HIF induces the expression of proangiogenic factors and stabilizes VEGF gene transcription.

The rheumatoid synovium expresses a variety of proangiogenic factors. [48,58] Some of these factors, such as FGF, PDGF, HGF, and EGF, are not specific to angiogenesis. Overexpression expression of angiogenesis factors, most prominently VEGF, angiopoietins -1 and -2, and the angiopoietin receptor, tie-2, is found in inflammatory joint disorders, including RA. [17,30,38,65,70,88] In addition, in the rheumatoid synovium, upregulation of adhesion molecules occurs[59] and is reduced with treatment, most commonly TNF-antagonist therapy.

 In vivo and in vitro, conventional DMARDs, as well as NSAIDs and glucocorticoids, have been demonstrated to have antiangiogenic effects. Proangiogenic mediator inhibition [12,32,95] or the delivery of cytokines that typically inhibit angiogenesis, such as angiostatin [81] and thrombospondin.

The risk of cardiovascular disease is increased in those with RA. Increased amounts of circulating inflammatory mediators in RA may promote endothelial cell activation and damage, contributing to endothelial dysfunction. Early-stage atheroma lesions are characterized by endothelial dysfunction. Atheroma development is strongly linked to abnormalities in arterial endothelial function. RA is linked to changes in endothelial cell morphology and function, as well as changes in the number and distribution of blood vessels [59].

 Even in young patients with minimal cardiovascular risk factors, endothelial impairment has been found in early-stage RA. [91] Treatment increases endothelial function, particularly with TNF-antagonists. [10,29,55] Endothelial progenitor cells (EPCs) are responsible for the development of new blood vessels in adults, and their absence has been linked to poor cardiovascular outcomes. They are also a biological marker for vascular function and increased cardiovascular risk. EPC levels in the peripheral blood of patients with active RA are lower. In individuals with inactive illness or those using TNF blockers or glucocorticoids, EPC levels are within normal limits [31].

Higher circulating VEGF-A and pentraxin-3 levels, as well as a lower angiopoietin-1/VEGF-A ratio, may be related to an increased risk of CKD due to the role of an angiogenic factor imbalance in the etiology of kidney disease [17,27,30,48,58,60,70]. Angiopoietin-1 treatment reduced tubular damage in unilateral ureteral obstruction [88], lowered albuminuria in streptozotocin-induced type 1 diabetes [38], and stabilized peritubular capillaries in folic acid nephropathy, albeit with profibrotic and inflammatory effects [65]. Angiopoietin-1 deficiency, along with microvascular stress, resulted in organ damage, increased angiogenesis, and fibrosis [59].

The findings on the connection between angiogenic factors and CKD in humans are somewhat inconsistent, most likely due to differences in sample size, research population, angiogenic factor sources, and covariables included in the studies. In a small cohort study, vascular endothelial growth factor (VEGF)-A predicted CKD progression in diabetic individuals [95]. However, another study found that VEGF expression was reduced in biopsied kidney tissue from diabetic nephropathy patients [12]. In dialysis patients, elevated soluble VEGF receptor-1 (sVEGFR-1) and decreased VEGFR-2 were related to mortality [32,81]. Angiopoietin-1 regulates endothelial cell migration, adhesion, and survival, and co-expression of angiopoietin-1 and VEGF promotes angiogenesis [91].

 In CKD patients, angiopoietin-1 levels are lower and angiopoietin-2 levels are higher [10,29]. Angiopoietin-2 [10,29,31,55] and angiopoietin-1 [31] have been linked to subclinical CVD in CKD. Angiopoietin-2 has been linked to an increased risk of death in CKD patients [10]. Pentraxin-3 can bind fibroblast growth factor-2 (FGF2) and operate as an FGF2 antagonist, inhibiting FGF2-dependent angiogenesis [55].

In patients with advanced renal cell carcinoma, sunitinib is a tyrosine kinase inhibitor (TKI) that targets tumor angiogenesis (RCC) [77].   

Angiogenesis is critical in the development of renal cell carcinoma, and clear cell renal cell carcinoma (CCRCC). Because of their anti-angiogenic properties, VEGF-targeted treatments have been implicated in the management of RCC and CCRCC. These treatments have also been shown to improve the survival rate of individuals with advanced kidney cancer [44,49].

Abnormal VEGF expression in renal cell carcinoma correlates with advanced stage, high nuclear grade, and increased microvascular density.

A study evaluating the effect of anti-angiogenic medicines, such as bevacizumab, found that circulating VEGF levels were reduced [85].

PDGF is a powerful mitogen that has also been linked to tumor angiogenesis [97]. PDGF expression is controlled during hypoxia by hypoxia-inducible factor 1 (HIF1) and other HIF1-independent processes.

CA9 is an enzyme that is generally activated by HIF-1 during hypoxia. CA9 expression was found to be a favorable predictive factor in patients with metastatic clear-cell RCC [50].

CCND1 has been demonstrated to be a HIF2 downstream target [99] and has been employed to detect HIF activation.

Angiogenesis indicators are useful in analyzing angiogenesis in tissue [44] and the expression of angiogenesis markers is frequently enhanced in kidney tumors. The majority of clear cell RCCs have mutations in the tumor suppressor gene VHL, which leads to increased expression of growth factors such as VEGF, platelet-derived growth factor (PDGF), insulin-like growth factor 2 (IGF2), and erythropoietin via downstream induction of transcription factors of hypoxia-inducible factor 1 (HIF) . The constitutive overexpression of these genes is believed to enhance the pathophysiological development of RCC by causing excessive vascularization and the inappropriate activation of signaling pathways that lead to cell proliferation and apoptosis inhibition.

Sunitinib is a tyrosine kinase inhibitor that targets VEGFR1, VEGFR2, VEGFR3, and PDGFR/. [14]. Sunitinib has been shown in several clinical trials to be particularly effective against clear cell RCC [37,38]. This medication has been demonstrated to produce an objective response in roughly 30-40% of patients [7]. Importantly, sunitinib therapy has been proven to improve PFS.

Acute kidney injury (AKI) occurs in 5% to 42% of individuals after heart surgery. Severe or protracted AKI has been linked to an increased risk of death, as have end-stage renal disease and earlier stages of chronic kidney disease (CKD). Renal hypoxia caused by capillary rarefaction is thought to have a role in the pathophysiology of the AKI-to-CKD transition.

 Before and after surgery, plasma concentrations of two proangiogenic markers (vascular endothelial growth factor A [VEGF] and placental growth factor [PGF]) and one antiangiogenic marker (soluble VEGF receptor 1 [VEGFR1]) were measured. After heart surgery, plasma VEGF concentrations decreased 2-fold, but PGF and VEGFR1 concentrations increased 1.5- and 8-fold, respectively.

High levels of pro-angiogenic markers, vascular endothelial growth factor A isoform (VEGF), and placental growth factor (PGF), in postoperative plasma, were independently related to a lower risk of AKI. High postoperative levels of an anti-angiogenic marker, soluble VEGF receptor 1 (sVEGFR1), also known as sFlt-1, on the other hand, were independently linked to an increased risk of AKI.       

VEGF is a crucial growth factor for angiogenesis, playing an important role in endothelial survival, peritubular capillary maintenance, and interstitial matrix modeling(69,81). VEGF is present largely in podocytes and the thick ascending limb, but it is also detected in proximal and distal tubules. VEGFRs (VEGFR1 and VEGFR2) are found in peritubular capillaries and glomerular capillary loops in endothelial cells. PGF is a proangiogenic chemical that stimulates the development of new blood vessels via the same receptor that VEGF does, VEGFR1. When sVEGFR1 attaches to VEGF or PGF, its activities are neutralized, and it acts as an antiangiogenic molecule [72].

VEGF production is enhanced in the presence of hypoxia via hypoxia-inducible factor-mediated transcriptional upregulation [83], and it represents an adaptive mechanism that promotes repair. The loss of angiogenic factors, particularly VEGF, has been linked to capillary loss following AKI. [83] Tubulointerstitial fibrosis occurs in animal models after capillary loss, implying that hypoxia caused by capillary rarefaction hinders redifferentiation of regenerated tubules.

Upregulation of VEGF improves kidney function [96], and VEGF injection after ischemia-reperfusion injury reduces capillary rarefaction [51].

In addition, VEGF treatment during cardiopulmonary bypass protects kidney function by improving renal microcirculation via nitric oxide-mediated vasodilation and inhibiting neutrophil accumulation and leukocyte adhesion [2]. High plasma VEGF levels, on the other hand, have been linked to higher mortality in experimental sepsis models [90].

Whereas sFlt-1 or anti-VEGF antibody administration has been linked to lower mortality [41]. Similarly, elevated serum VEGF levels have been linked to an increased risk of AKI and death in individuals with influenza and acute respiratory distress syndrome [4].

Serum PGF levels were not observed to be significantly higher in AKI compared to controls in short cross-sectional research [98]. Furthermore, giving a single angiogenic agent may promote the growth of aberrant vasculature and produce inflammation, exacerbating hypoxia and tubulointerstitial fibrosis [83].

Anti-VEGF medications have been linked to the development of hypertension, proteinuria, and kidney injury in oncology. Similar results can be seen when sFlt-1 is administered during pregnancy.

Hypoglycemia enhances VEGF expression, which returns to normal after re-equilibration of the glucose concentration [68,76]. This is most likely caused by an increase in intracellular CA2+ levels in a glucose-depleted environment, which results in the activation of protein kinase C. This mechanism activates Angiopoiten-1, resulting in increased VEGF expression [64]. Not only does hypoglycemia promote VEGF expression, but so does hyperglycemia, both of which can increase VEGF production[37,44].

The presence of inflammatory cells such as macrophages and neutrophils is enough to cause angiogenesis. Following cardiac necrosis, an influx of inflammatory cells such as macrophages, monocytes, and platelets causes the release of cytokines capable of boosting the expression of fibroblast growth factor and vascular endothelial growth factor [78,79]. The vascular endothelial growth factor can activate and recruit additional macrophages to stimulate the inflammatory response and angiogenesis.

The isolation of tumor factors that promote mitogenic activity in endothelial cells led to the discovery of angiogenic factors [22,23,26]. They are induced by a wide range of cells, and their functions include development and tumor angiogenesis. Angiogenic growth factors are so named because of their propensity to generate cell proliferation in vitro, which contributes to the process of angiogenesis in vivo, as evidenced by animal model studies. We shall discuss a few of these development factors briefly:

The first angiogenic growth factor found as a member of a family now consists of at least 20 compounds with significant mitogenic potentials, including some of the most potent angiogenic peptides [22,23,26]. Smooth muscle cells and vascular endothelial cells create them. The ability of the FGF family to interact with heparin-like glycosaminoglycan of the extracellular matrix is one of its characteristics [22]. FGF-1 and FGF-2 are the two most studied isoforms [39,40,92].

It was first isolated as a vascular permeability factor from tumor cell ascites [18]. It is currently recognized as a multifunctional peptide capable of promoting both in vivo and in vitro receptor-mediated endothelial cell proliferation and angiogenesis. It is essential for embryonic vascular development as well as adult pathophysiology. VEGF is a family of five members, and their action is mediated by three receptors (VEGFR) [11,19,71,86].

It has limited angiogenic activity in vitro, although it appears that PLGF and VEGF co-express in vivo [8,62,81].

Angiopoietin1 (Ang1) is expressed in tissue near blood arteries, implying a paracrine method of action. Angiopoietin 2 (ANG2) is present at tissue remodeling sites [9,16,54].

The effect of VEGF on endothelial cells in humans is mediated by two membrane-spanning receptors, VEGFR1 and VEGFR2. Both receptors have strong VEGF affinity [52,75,80]. VEGFR1 promotes cell motility, has a function in blood vessel organization, and regulates monocyte and macrophage gene expression. While VEGFR2 is important in mitogenesis, endothelial cell differentiation, cell migration encouragement, and vascular permeability increase.

VEGFs and their receptor VEGFR-2 (KDR) have a substantial impact on the process of angiogenesis, among other growth factors such as PDGFs, FGFs, and cytokines. After activation, KDR undergoes auto phosphorylation, which leads to endothelial cell proliferation, tumor angiogenesis, tumor development, and metastasis.

VEGFR-2 overexpression has been seen in a variety of cancers, including breast cancer, cervical cancer, non-small cell lung cancer, hepatocellular carcinoma, renal carcinoma, and others. Several VEGFR-2 inhibitors have been developed throughout the last decade. Angiogenesis suppression by VEGFR-2 inhibition is a new technique for developing selective and targeted anticancer medicines.

Many tumors rely on an angiogenic switch after reaching a diameter of 1–2 mm, making tumor angiogenesis one of the hallmarks of early malignancy [93]. As a result, the ability to visualize and quantify tumor angiogenesis may not only allow antiangiogenic treatment monitoring in cancer patients, but it may also be an elegant approach for screening and detecting cancer at an early, still curable stage, just after the angiogenic switch in tumor progression.

Several molecular angiogenic markers are overexpressed in tumors and may be exploited as early cancer detection targets. v3 Integrin, endoglin, and vascular endothelial growth factor receptor (VEGFR) 2 are three well-studied molecular indicators of tumor angiogenesis [34,63,84]. These angiogenic markers are seen on tumor vascular endothelial cells in a variety of solid tumors, including breast [21,74], ovarian [28,47], and pancreatic cancer, and are thought to be key factors in tumor angiogenesis. Integrin v3, a glycoprotein composed of a noncovalently bound subunit, forms a heterodimeric transmembrane receptor for extracellular matrix components such as fibronectin, fibrinogen, von Willebrand factor, vitronectin, and proteolyzed collagen and laminin [36,67].

These extracellular matrix components stimulate signaling cascades that influence gene expression, cytoskeletal architecture, cell adhesion, and cell survival, causing tumor cells to become more invasive, migratory, and capable of surviving in a variety of microenvironments [67]. Endoglin (CD105) is a transmembrane glycoprotein that is mostly expressed in endothelial cells that are actively undergoing angiogenesis, such as tumor endothelial cells [90]. It is a component of the TGF-1 receptor complex, a pleiotropic cytokine involved in cellular proliferation, differentiation, and migration [24]. Endoglin inhibition increased TGF-1's ability to restrict growth, migration, and the ability of developed endothelial cells to form capillaries.

VEGFR2 is a tyrosine kinase endothelial receptor that is activated by VEGF A. The VEGF/VEGFR2 pathway activates various signaling networks, resulting in endothelial cell survival, mitogenesis, migration, differentiation, and vascular permeability [5].

It is essential in developing novel molecular imaging methods aimed at seeing tumor angiogenesis markers that are overexpressed in early-stage cancer for screening reasons. Knowledge of the temporal expression levels of tumor angiogenic markers could also be relevant for drug development and personalizing future treatment regimens in cancer patients.

Targeted contrast material–enhanced ultrasonography (US) is a potential noninvasive molecular imaging technique that permits in vivo assessment of tumor angiogenesis molecular markers [33,53,94]. Because the contrast chemicals used for this imaging method have a diameter of several micrometers [66], they remain inside the vascular compartment, allowing for the exclusive observation of angiogenesis-related molecular markers expressed on tumor vascular endothelial cells.

By all accounts and based on verified results, it appears that understanding the activation of proangiogenic factors, estimating the pathway of angiogenesis, and studying the influence of antiangiogenic factors may aid in the development of an effective treatment for diseases with pathological angiogenic conditions, especially for several malignancies.

Angiogenesis is thus a potential therapeutic target. The potential use of several angiogenesis inhibitors is now being studied in clinical trials. A greater understanding of the biology of angiogenesis may lead to the identification of new therapeutic targets for a variety of disorders connected with this complex process.

Tumor angiogenesis is important in tumor growth and metastasis. Tumor angiogenesis is a complex process involving several components and several distinct or similar signal pathways. Despite fast development in the field, there are numerous unanswered questions about the molecular process of tumor angiogenesis. Once we fully comprehend the precise activities of these pro-and anti-angiogenic molecules in tumor angiogenesis, therapeutic use of those innovative study findings for tumor therapy will be achievable.

1. Angiogenesis inhibitors. National Cancer Institute. (n.d.). Retrieved January 30, 2022.
2. Bai Y, Zhang Y, Yang S, et al. (2018) Protective effect of vascular endothelial growth factor against cardiopulmonary bypass?associated acute kidney injury in beagles. Exper Therap Med. 15 (1): 963-969.
3. Barczy?ski B, ?wikli?ska A, Mazurek M, et al. (2009) Expression of selected angiogenesis markers and modulators in pre-, peri-and postmenopausal women with ovarian cancer. Ginekol Pol. 80 (2): 93-8.
4. Bautista E, Arcos M, Jimenez-Alvarez L, et al. (2013) Angiogenic and inflammatory markers in acute respiratory distress syndrome and renal injury associated to A/H1N1 virus infection. Exp Mol Pathol. 94 (3): 486-492.
5. Bernabeu C, Lopez-Novoa JM, Quintanilla M (2009) The emerging role of TGF-β superfamily coreceptors in cancer. Biochim Biophys Acta. 1792 (10): 954-973.
6. Bornstein P (1995) Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J Cell Biol. 130 (3): 503-506.
7. Bukowski RM, Eisen T, Szczylik C, et al. (2007) Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis. J Clinic Oncol. 25 (18): 5023.
8. Cao Y, Ji WR, Qi P, et al. (1997) Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun. 235 (3): 493-498.
9. Cao Y, Linden P, Shima D, et al. (1996) In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor. J Clin Invest. 98 (11): 2507-2511.
10. Cardillo C, Schinzari F, Mores N, et al. (2006) Intravascular tumor necrosis factor α blockade reverses endothelial dysfunction in rheumatoid arthritis. Clin Pharmacol Ther. 80 (3): 275-281.
11. Carmeliet P, Collen D (1997) Molecular analysis of blood vessel formation and disease. Am J Physiol. 273 (5): H2091-2104.
12. Chen Y, Donnelly E, Kobayashi H, et al. (2005) Gene therapy targeting the Tie2 function ameliorates collagen?induced arthritis and protects against bone destruction. Arthritis Rheum. 52 (5): 1585-1594.
13. Clavel G, Boisser M C (2008) Angiogenesis markers in rheumatoid arthritis.  Fut Rheu. 2 (3): 153-159.
14. Coppin C, Porzsolt F, Awa A, et al. (2005) Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 200 (6): A38-39.
15. Costa C, Incio J, Soares R (2007) Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis. 10 (3): 149-166.
16. Davis S, Aldrich TH, Jones PF, et al. (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 87 (7): 1161-1169.
17. DeBusk LM, Chen Y, Nishishita T, et al. (2003) Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor α–induced angiogenesis in rheumatoid arthritis. Arthritis Rheum. 48 (9): 2461-2471.
18. Engelmann GL, Dionne CA, Jaye MC (1993) Acidic fibroblast growth factor and heart development. Role in myocyte proliferation and capillary angiogenesis. Circ Res. 72 (1): 7-19.
19. Ferrara N, Houck K, Jakeman LY, et al. (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 13 (1): 18-32.
20. Ferrara N (1999) Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 56 (3): 794-814.
21. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 25 (4): 581-611.
22. Folkman J (1984) Angiogenesis. Biol Endothel Cells. 27 (3): 412-428.
23. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med. 285 (21): 1182-1186.
24. Fonsatti E, Altomonte M, Arslan P, et al. (2003) Endoglin (CD105): a target for anti-angiogenetic cancer therapy. Curr Drug Targets. 4 (4): 291-296.
25. Frazier WA (1991) Thrombospondins. Current opinion in cell biology. 3 (5): 792-799.
26. Friesel RE, Maciag T (1995) Molecular mechanisms of angiogenesis: fibroblast growth factor signal transduction. FASEB J. 9 (10): 919-925.
27. Gaber T, Dziurla R, Tripmacher R, et al. (2005) Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do!. Ann Rheum Dis. 64 (7): 971-980.
28. Gómez-Raposo C, Mendiola M, Barriuso J, et al. (2009) Angiogenesis and ovarian cancer. Clinic Trans Oncol. 11 (9): 564-571.
29. Gonzalez-Gay MA, Garcia-Unzueta MT, De Matias JM, et al. (2006) Influence of anti-TNF-alpha infliximab therapy on adhesion molecules associated with atherogenesis in patients with rheumatoid arthritis. Clin Exp Rheumatol. 24 (4): 373-379.
30. Gravallese EM, Pettit AR, Lee R, et al. (2003) Angiopoietin-1 is expressed in the synovium of patients with rheumatoid arthritis and is induced by tumour necrosis factor α. Ann Rheum Dis. 62 (2): 100-107.
31. Grisar J, Aletaha D, Steiner CW, et al. (2007) Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy. Ann Rheum Dis. 66 (10): 1284-1288.
32. Grosios K, Wood J, Esser R, et al. (2004) Angiogenesis inhibition by the novel VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222584, causes significant anti-arthritic effects in models of rheumatoid arthritis. Inflamm Res. 53 (4): 133-142.
33. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 23 (5): 1011-1027.
34. Hodivala-Dilke K (2008) αvβ3 integrin and angiogenesis: a moody integrin in a changing environment. Curr Opin Cell Biol. 20 (5): 514-519.
35. HOGG PJ, HOTCHKISS KA, JIMÉNEZ BM, et al. (1997) Interaction of platelet-derived growth factor with thrombospondin 1. Biochemical J. 326 (3): 709-716.
36. Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer. 2 (2): 91-100.
37. Hoshi S, Nomoto K, Kuromitsu J, et al. (2002) High glucose induced VEGF expression via PKC and ERK in glomerular podocytes. Biochem Biophys Res Commun. 290 (1) :177-84.
38. Ikeda M, Hosoda Y, Hirose S, et al. (2000) Expression of vascular endothelial growth factor isoforms and their receptors Flt?1, KDR, and neuropilin?1 in synovial tissues of rheumatoid arthritis. J Pathol. 191 (4): 426-433.
39. Imamura T, Engleka K, Zhan X, et al. (1990) Recovery of mitogenic activity of a growth factor mutant with a nuclear translocation sequence. Science. 249 (4976): 1567-1570.
40. Jaye M, Howk R, Burgess W, et al. (1986) Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization. Science. 233 (4763): 541-545.
41. Jeong SJ, Han SH, Kim CO, et al. (2013) Anti-vascular endothelial growth factor antibody attenuates inflammation and decreases mortality in an experimental model of severe sepsis. Crit Care. 17 (3): 1-8.
42. Khosravi Shahi P, Soria Lovelle A, Perez Manga G (2009) Tumoral angiogenesis and breast cancer. Clin Trans Oncol. 11 (3): 138-142.
43. Kim HL, Seligson D, Liu X, et al. (2005) Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J urol. 173 (5): 1496-1501.
44. Kim NH, Jung HH, Cha DR, et al. (2000) Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells. J Endocrinol. 165 (3): 617-624.
45. Koch AE, Distler O, (2007) Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther. 9 (2): 1-9.
46. Koch AE (2000) The role of angiogenesis in rheumatoid arthritis: recent developments. Ann Rheum Dis. 59 (suppl 1): i65-i71.
47. Lampinen AM, Virman JP, Bono P, et al. (2017) Novel angiogenesis markers as long-term prognostic factors in patients with renal cell cancer. Clin Genitourin Cancer. 15 (1): e15-24.
48. Leibovich BC, Sheinin Y, Lohse CM, et al. (2007) Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. J Clin Oncol. 25 (30): 4757-4764.
49. Leonard EC, Friedrich JL, Basile DP, (2008) VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am J Physiol Renal Physiol. 295 (6): F1648-F1657.
50. Li J, Perrella MA, Tsai JC, et al. (1995) Induction of Vascular Endothelial Growth Factor Gene Expression by Interleukin-1 β in Rat Aortic Smooth Muscle Cells. J Biol Chem. 270 (1): 308-312.
51. Lindner JR (2004) Microbubbles in medical imaging: current applications and future directions. Nat Rev Drug Discov. 3 (6): 527-533.
52. Maisonpierre PC, Suri C, Jones PF, et al. (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 277 (5322): 55-60.
53. Ma?ki-Peta?ja? KM, Hall FC, Booth AD, et al. (2006) Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti–tumor necrosis factor-α therapy. Circulation. 114 (11): 1185-1192.
54. Mansour SG, Zhang WR, Moledina DG, et al. (2019) The association of angiogenesis markers with acute kidney injury and mortality after cardiac surgery. Am J Kidney Dis. 74 (1): 36-46.
55. Marech I, Leporini C, Ammendola M, et al. (2016) Classical and non-classical proangiogenic factors as a target of antiangiogenic therapy in tumor microenvironment. Cancer let. 380 (1): 216-226.
56. Maruotti N, Crivellato E, Cantatore FP, et al. (2007) Mast cells in rheumatoid arthritis. Clinical rheumatology. 26 (1): 1-4.
57. Middleton J, Americh L, Gayon R, et al. (2004) Endothelial cell phenotypes in the rheumatoid synovium: activated, angiogenic, apoptotic and leaky. Arthritis Res Ther. 6 (2): 1-3.
58. Mor F, Quintana FJ, Cohen IR (2004) Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol. 172 (7): 4618-4623.
59. Mosher DF (1990) Physiology of thrombospondin. Annual review of medicine. 41 (1): 85-97.
60. Neufeld G, Cohen T, Gengrinovitch S, et al. (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13 (1): 9-22.
61. Palmowski M, Huppert J, Ladewig G, et al. (2008) Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects. Mol Cancer Ther. 7 (1): 101-109.
62. Park SH, Kim KW, Lee YS, et al. (2001) Hypoglycemia-induced VEGF expression is mediated by intracellular Ca2+ and protein kinase C signaling pathway in HepG2 human hepatoblastoma cells. Int J mol med. 7 (1): 91-97.
63. Pettit AR, Gravallese EM, Manning C, et al. (2001) Angiopoietin-1 is expressed in RA synovium and is induced by TNF-alpha in cultured synovial fibroblasts. Arthrit Rheumat. 62 (2): 45-46.
64. Pysz MA, Foygel K, Rosenberg J, et al. (2010) Antiangiogenic cancer therapy: monitoring with molecular US and a clinically translatable contrast agent (BR55). Radiology. 256 (2): 519-527.
65. Saif MW (2006) Anti-angiogenesis therapy in pancreatic carcinoma. Jop. 7 (2): 163-173.
66. Satake S, Kuzuya M, Miura H, et al. (1998) Up?regulation of vascular endothelial growth factor in response to glucose deprivation. Biol Cell. 90 (2): 161-168.
67. Schrijvers BF, Flyvbjerg A, De Vriese AS (2004) The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int. 65 (6): 2003-2017.
68. Scott BB, Zaratin PF, Colombo A, et al. (2002) Constitutive expression of angiopoietin-1 and-2 and modulation of their expression by inflammatory cytokines in rheumatoid arthritis synovial fibroblasts. J Rheumatol. 29 (2): 230-239.
69. Senger DR, Galli SJ, Dvorak AM, (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 219 (4587): 983-985.
70. Shibuya M (2006) Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis. 9 (4): 225-230.
71. Shim WS, Ho IA, Wong PE (2007) Angiopoietin: a TIE (d) balance in tumor angiogenesis. Mol Cancer Res. 5 (7): 655-665.
72. Sledge GW, Rugo HS, Burstein HJ (2006) The role of angiogenesis inhibition in the treatment of breast cancer. Clin Adv Hematol Oncol. 4 (21): 1–10.
73. Soker S, Takashima S, Miao HQ, et al. (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.
74. Sone H, Kawakami Y, Okuda Y, et al. (1996) Vascular endothelial growth factor is induced by long-term high glucose concentration and up-regulated by acute glucose deprivation in cultured bovine retinal pigmented epithelial cells. Biochem Biophys Res Commun. 221 (1): 193-198.
75. Stubbs C, Bardoli AD, Afshar M, et al. (2017) A study of angiogenesis markers in patients with renal cell carcinoma undergoing therapy with sunitinib. Anticancer Res. 37 (1): 253-259.
76. Sunderkötter C, Beil W, Roth J, et al. (1991) Cellular events associated with inflammatory angiogenesis in the mouse cornea. Am J Pathol. 138 (4): 931-939.
77. Sunderkötter C, Goebeler M, Schulze-Osthoff K, et al. (1991) Macrophage-derived angiogenesis factors. Pharmacol Ther. 51 (2): 195-216.
78. Suri C, Jones PF, Patan S, et al. (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 87 (7): 1171-1180.
79. Takahashi H, Kato K, Miyake K, et al. (2005) Adeno-associated virus vector-mediated anti-angiogenic gene therapy for collagen-induced arthritis in mice. Clin Exp Rheumatol. 23 (4): 455-467.
80. Takakura N, Watanabe T, Suenobu S, et al. (2000) A role for hematopoietic stem cells in promoting angiogenesis. Cell. 102 (2): 199-209.
81. Tanaka S, Tanaka T, Nangaku M (2014) Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol. 307 (11): F1187-F1195.
82. Ten Dijke P, Goumans MJ, Pardali E (2008) Endoglin in angiogenesis and vascular diseases. Angiogenesis. 11 (1): 79-89.
83. Terakawa T, Miyake H, Kusuda Y, et al. (2013) Expression level of vascular endothelial growth factor receptor-2 in radical nephrectomy specimens as a prognostic predictor in patients with metastatic renal cell carcinoma treated with sunitinib. Urol Oncol. 31 (4): 493-498.
84. Tischer E, Gospodarowicz D, Mitchell R, et al. (1989) Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem Biophys Res Commun. 165 (3): 1198-1206.
85. Tsuchiya N, Sato K, Akao T, et al. (2001) Quantitative analysis of gene expressions of vascular endothelial growth factor-related factors and their receptors in renal cell carcinoma. Tohoku J Exper Med. 195 (2): 101-113.
86. Uchida T, Nakashima M, Hirota Y, et al. (2000) Immunohistochemical localisation of protein tyrosine kinase receptors Tie-1 and Tie-2 in synovial tissue of rheumatoid arthritis: correlation with angiogenesis and synovial proliferation. Ann Rheum Dis. 59 (8): 607-614.
87. Van der Flier A, Sonnenberg A (2001) Function and interactions of integrins. Cell Tissue Res. 305 (3): 285-298.
88. van der Flier M, van Leeuwen HJ, van Kessel KP, et al. (2005) Plasma vascular endothelial growth factor in severe sepsis. Shock. 23 (1): 35-38.
89. Vaudo G, Marchesi S, Gerli R, et al. (2004) Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity. Ann Rheum Dis. 63 (1): 31-35.
90. Wadzinski MG, Folkman J, Sasse J, et al. (1987) Heparin-binding angiogenesis factors: detection by immunological methods. Clin Physiol Biochem. 5 (4): 200-209.
91. Warren RS, Yuan H, Matli MR, et al. (1996) Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma. J Biol Chem. 271 (46): 29483-29488.
92. Willmann JK, Van Bruggen N, Dinkelborg LM, et al. (2008) Molecular imaging in drug development. Nat Rev Drug Discov. 7 (7): 591-607.
93. Yoo SA, Bae DG, Ryoo JW, et al. (2005) Arginine-rich anti-vascular endothelial growth factor (anti-VEGF) hexapeptide inhibits collagen-induced arthritis and VEGF-stimulated productions of TNF-α and IL-6 by human monocytes. J Immunol. 174 (9): 5846-5855.
94. Yoshida M, Nakamichi T, Mori T, et al. (2019) Low-energy extracorporeal shock wave ameliorates ischemic acute kidney injury in rats. Clin Exp Nephrol. 23 (5): 597-605.
95. Yu JH, Ustach C, ChoiKim HR. (2003) Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol. 36 (1): 49-59.
96. Zakiyanov O, Kriha V, Vachek J, et al. (2013) Placental growth factor, pregnancy-associated plasma protein-A, soluble receptor for advanced glycation end products, extracellular newly identified receptor for receptor for advanced glycation end products binding protein and high mobility group box 1 levels in patients with acute kidney injury: a cross sectional study. BMC Nephrolo. 14 (1): 1-1.
97. Zatyka M, Silva NF, Clifford SC, et al. (2002) Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Cancer Res. 62 (13): 3803-3811.

 PDF