Biomolecules in Vascular Endothelial Growth Factor: History
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Anna K. Rekowska
,
Karolina Obuchowska
,
Magdalena Bartosik
,
Żaneta Kimber-Trojnar
,
Magdalena Słodzińska
,
Magdalena Wierzchowska-Opoka
,
Bożena Leszczyńska-Gorzelak

Vascular endothelial growth factor (VEGF) is a protein belonging to the VEGF family, which is a large group of molecules consisting of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PlGF). VEGF is a subfamily of growth factors (GF). VEGF is a multitasking protein that mediates both vasculogenesis (the process of blood vessel formation from endothelial progenitor cells in embryos and adults during tumor growth) and angiogenesis (the formation of blood vessels from pre-existing vessels formed during vasculogenesis, consisting of sprouting and splitting).

  • biomolecules
  • VEGF
  • PlGF

1. Types of  VEGF family members 

Types of VEGF family members [1][2] include:
  • VEGF-A (also called VEGF) is the best-known and most important factor, mainly involved in vasculogenesis and angiogenesis. The main targets of VEGF-A are endothelial cells, in which it stimulates migration and mitosis, inhibits apoptosis, and dilates vessels with NO. There are many specific isoforms of VEGF-A, with various features, formed during alternative splicing. VEGF-A is secreted by kidney mesangial cells, macrophages, cells of the retina, osteoblasts, keratinocytes, platelets, and many others. VEGF-A is bound to extracellular matrix elements, and proteolytic enzymes (metalloproteinases and plasmin) can release free, diffusible forms of it, which are active in the extracellular environment.
  • VEGF-B is primarily involved in embryonic tissues in the development of the cardiovascular system. In adult individuals, it takes part in myocardial remodeling.
  • VEGF-C initiates the development of lymphatic tissue during lymphangiogenesis but is not a strong angiogenic factor.
  • VEGF-D, similar to VEGF-C, controls lymphangiogenesis, but in the lungs.
  • VEGF-E (viral) is not found in humans.
Different types of VEGF require various types of VEGF receptors. All of them are tyrosine kinase receptors, consisting of three parts: a transmembrane domain composed of the cell membrane, an extracellular domain for binding VEGF from ECM, and an internal domain involved in the phosphorylation of tyrosine. Types of VEGF receptors include [1][2]:
  • VEGFR-1 (Flt-1) is responsible for binding VEGF-A, VEGF-B, and PlGF. VEGFR-1 has also been produced in the ECM as a soluble isoform (sVEGFR-1/sFlt-1) and, similarly to the transmembrane type, can bind the same factors. Surprisingly, sFlt-1 can cooperate with VEGFR-2 to decrease its activity. Consequently, sVEGFR-1 employs anti-angiogenic, anti-edema, and anti-inflammatory activities, and its dysregulation has been connected with other pathological processes. The pathogenesis of preeclampsia, which usually occurs in the last trimester of pregnancy and is linked to sVEGFR-1 production because of the placenta, and subsequent neutralization of VEGF-A and PIGF signaling. A poor quantity of sVEGFR-1 to VEGF-A has been tied to excessive tumor malignancy/invasiveness and inferior patient survival. Additionally, sVEGFR-1 may play a proangiogenic and protumoral role as well, through the activation of β1 integrin, which stimulates endothelial cell adhesion and chemotaxis [3].
  • VEGFR-2 (KDR/Flk-1) binds VEGF-A and, on special occasions, VEGF-E, C, and D. Its main function is to initiate vasculogenesis and can be found not only on epithelial cells but also on hemangioblasts.
  • VEGFR-3 (Flt-4) is a receptor for VEGF-C and VEGF-D and is a mediator in the lymphangiogenesis process.

2. Role of VEGF

Tumor angiogenesis plays a significant role in cancer progression and metastasis [1][2][4]. The development of a tumor mass requires oxygen and nutrient delivery, which necessitates the growth of new blood vessels. This problem is partly solved by increasing the expression of VEGF/VEGFR produced by cancer cells [5]. Therefore, as VEGFR-1 has a crucial role in tumor-associated angiogenesis, it is also involved in physiological angiogenesis [2]. Pathological lymphangiogenesis caused by the connection between VEGF-C/VEGF-D and their receptor (VEGFR-3) is also involved in tumor progression. New networks of lymphatic vessels create opportunities for metastatic cells to spread to distant tissues and lymph nodes. The expression VEGF has many regulatory factors, one of which is the hypoxia-inducible factor (HIF), which is triggered by a hypoxic environment [6]. Besides VEGF, HIF can also activate more proangiogenic agents such as angioproteins, TGF-β, TNF-α, and basic FGF [1]. The last-mentioned one can induce VEGF synthesis, and together they have synergy in action. Decreased pH, low levels of glucose, hypertension, and inflammation can also intensify the production of VEGF and its receptors. In metastatic processes, other molecules are involved, mainly those that disturb the stability of cell junctions, such as cadherins and matrix metalloproteinases, which are induced by VEGF. These signaling pathways are commonly documented in various types of cancers originating from different organs and tissues, e.g., lungs, liver, skin, brain, kidneys, pancreas, bones, gastrointestinal tract, bone marrow, breast, OC, and prostate [2][7][8][9]. According to a study by Liang et al., the proliferation of cells from various breast cancer cell lines and inhibition of apoptosis by increasing Bcl-2 levels are connected with VEGF secretion. A higher concentration of VEGF, probably bound to sex steroid hormones, is associated with a poor response to hormonal therapy in treatment and worse survival [9][10].
Implantation of the embryo during pregnancy leads to the formation of a new organ, the placenta. Trophoblast villi invade the top layer of the uterus, called the decidua. Proper placental development also involves the development of new blood vessels. Extravillous cytotrophoblast cells proliferate and interact with spiral arterioles in the uterine wall, subsequently remodeling them and incorporating them into the epithelial cells. This creates a connection between the maternal and fetal blood supplies necessary for exchanging substrates for fetal growth and metabolic products produced by it [11].
Angiogenesis in the placenta and tumors is based on similar pathways, including VEGF, PlGF, and their receptors, and their levels are regulated by various hormonal and nonhormonal agents. However, it is worth mentioning that the level of PlGF in normal placental development is significantly higher compared to VEGF levels [12]. Disorders in the correlation between levels of pro-angiogenic factors, receptors, and their soluble forms may be one of the reasons for PAS. Tseng et al. studied the differential expression of vascular endothelial growth factor, placenta growth factor, and their receptors in placentae from pregnancies complicated by PAS. The results of their work showed no difference in the content of PlGF and sFlt-1 in samples taken from patients with disturbed and undisturbed placentation. In the second conclusion, they suggested that women with PAS have a lower quantity of sVEGFR-2 and higher expression of VEGF than the control group [12].
Wang et al. also dealt with similar issues exploring the association of VEGF and sFlt-1 and their use for the diagnosis of pernicious placenta previa (PPP) and this condition complicated by placenta accreta/increta [13]. The authors indicated that VEGF was negatively correlated with sFlt-1 in the serum of PPP patients. Moreover, numerous past experiments showed that the decrease of VEGF and its receptors and the increase of sFlt-1 in serum could specifically indicate the presence of placenta accreta. According to the article, similar results could be found. The authors discovered that VEGF concentration was the lowest in PPP correlated with placenta increta and continuously increased in PPP combined with placenta accreta, PPP alone, and healthy controls, and there was a remarkable variance between the groups. Therefore, sFlt-1 had the highest concentration in the PPP combined with the placenta increta group, followed by PPP combined with placenta accreta and the PPP group, which had the lowest concentration in the control group [13].
Disorders in proangiogenic factors can lead to not only invasive growth of the placenta in PAS but also other conditions with faulty placenta development. Increased VEGFR-1 is associated with a higher sFlt1 concentration, which plays a negative role in angiogenesis by binding VEGF-A and PlGF [1][12][14]. Preeclampsia is a disorder that mainly occurs in the third trimester of pregnancy and is a life-threatening medical condition for both mother and fetus [2]. The main symptom is higher than normal blood pressure, which indicates incorrect functioning of other organs and may lead to proteinuria, liver dysfunction, visual disturbances, and other complications [15]. Research shows an increased sFlt-1 level in patients with preeclampsia [1][2][14][15][16].

This entry is adapted from the peer-reviewed paper 10.3390/cancers15092618

References

  1. Melincovici, C.S.; Bo, A.B.; Mihu, C.; Istrate, M.; Moldovan, I.-M.; Roman, A.L.; Mihu, C.M. Vascular Endothelial Growth Factor (VEGF)—Key Factor in Normal and Pathological Angiogenesis. Rom. J. Morphol. Embryol. 2018, 59, 455–467.
  2. Ceci, C.; Atzori, M.G.; Lacal, P.M.; Graziani, G. Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models. Int. J. Mol. Sci. 2020, 21, 1388.
  3. Liao, L.; Zhao, X.; Zhou, M.; Deng, Y.; Li, Y.; Peng, C. SFlt-1: A Double Regulator in Angiogenesis-Related Diseases. Curr. Pharm. Des. 2021, 27, 4160–4170.
  4. Patan, S. Vasculogenesis and Angiogenesis. Cancer Treat. Res. 2004, 117, 3–32.
  5. Weitzner, O.; Seraya-Bareket, C.; Biron-Shental, T.; Fishamn, A.; Yagur, Y.; Tzadikevitch-Geffen, K.; Farladansky-Gershnabel, S.; Kidron, D.; Ellis, M.; Ashur-Fabian, O. Enhanced Expression of AVβ3 Integrin in Villus and Extravillous Trophoblasts of Placenta Accreta. Arch. Gynecol. Obstet. 2021, 303, 1175–1183.
  6. Macklin, P.S.; McAuliffe, J.; Pugh, C.W.; Yamamoto, A. Hypoxia and HIF Pathway in Cancer and the Placenta. Placenta 2017, 56, 8–13.
  7. Devery, A.M.; Wadekar, R.; Bokobza, S.M.; Weber, A.M.; Jiang, Y.; Ryan, A.J. Vascular Endothelial Growth Factor Directly Stimulates Tumour Cell Proliferation in Non-Small Cell Lung Cancer. Int. J. Oncol. 2015, 47, 849–856.
  8. Adamcic, U.; Skowronski, K.; Peters, C.; Morrison, J.; Coomber, B.L. The Effect of Bevacizumab on Human Malignant Melanoma Cells with Functional VEGF/VEGFR2 Autocrine and Intracrine Signaling Loops. Neoplasia 2012, 14, 612-IN16.
  9. Liang, Y.; Brekken, R.A.; Hyder, S.M. Vascular Endothelial Growth Factor Induces Proliferation of Breast Cancer Cells and Inhibits the Anti-Proliferative Activity of Anti-Hormones. Endocr. Relat. Cancer 2006, 13, 905–919.
  10. Gasparini, G. Prognostic Value of Vascular Endothelial Growth Factor in Breast Cancer. Oncologist 2000, 5, 37–44.
  11. Guibourdenche, J.; Fournier, T.; MalassinĂŠ, A.; Evain-Brion, D. Development and Hormonal Functions of the Human Placenta. Folia Histochem. Cytobiol. 2009, 47, 35–40.
  12. Tseng, J.J.; Chou, M.M.; Hsieh, Y.T.; Wen, M.C.; Ho, E.S.C.; Hsu, S.L. Differential Expression of Vascular Endothelial Growth Factor, Placenta Growth Factor and Their Receptors in Placentae from Pregnancies Complicated by Placenta Accreta. Placenta 2006, 27, 70–78.
  13. Wang, N.; Shi, D.; Li, N.; Qi, H. Clinical Value of Serum VEGF and SFlt-1 in Pernicious Placenta Previa. Ann. Med. 2021, 53, 2041–2049.
  14. Manna, C.; Lacconi, V.; Rizzo, G.; De Lorenzo, A.; Massimiani, M. Placental Dysfunction in Assisted Reproductive Pregnancies: Perinatal, Neonatal and Adult Life Outcomes. Int. J. Mol. Sci. 2022, 23, 659.
  15. Ives, C.W.; Sinkey, R.; Rajapreyar, I.; Tita, A.T.N.; Oparil, S. Preeclampsia—Pathophysiology and Clinical Presentations: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2020, 76, 1690–1702.
  16. Shibuya, M. Involvement of Flt-1 (VEGF Receptor-1) in Cancer and Preeclampsia. Proc. Jpn. Acad. Ser. B 2011, 87, 167–178.
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