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Role of Vascular Endothelial Growth Factor in Ovarian Function in Bovine

Rupali Rautela Rahul Katiyar
Vol 8(1), 32-38

Vascular Endothelial Growth Factor (VEGF) plays an important in ovarian function from follicular development to ovulation. It is an angiogeneic factor that stimulates vessel formation and increases vascular permeability to supply nutrition and oxygen to developing follicle. During luteal phase, VEGF expression is required for corpus luteum (CL) development and function. Inhibition of VEGF expression results in abnormal angiogenesis and hence affects ovarian structure. Therefore, understanding the action of VEGF along with action of hormones influencing its expression is necessary to assimilate ovarian pathology.

Keywords : Bovine Hormones Follicle Vascular Endothelial Growth Factor


In cattle, follicular development is characterized by recruitment of cohort of follicles, selection of dominant follicle and its growth and maturation till it reaches preovulatory stage and atresia of the other subordinate follicles (Berisha and Schams, 2005). Following ovulation, certain morphological and biochemical changes occur in theca and granulosa cells leading to formation of corpus luteum (CL). This complex mechanism is controlled by the pituitary hormones along with locally produced steroid hormones, peptides and growth factors (Fortune, 1994). Among the various growth factor, vascular endothelial growth factor (VEGF), a potent and specific angiogenic factor, is found essential for the follicular growth and development and CL formation (Zimmermann et al., 2003; Berisha and Schams, 2005). Several intraovarian factors play crucial role in modulation of VEGF expression. Cytokines such as Transforming Growth Factor (TGF) and Bone Morphogenic Proteins (BMP) induce expression of VEGF in endothelial cells (Kuo et al., 2011) as well as in granulosa cells (Akiyama et al., 2014) thereby stimulate vascularization in growing follicle. Similarly, upregulation of VEGF expression by polypeptides Nerve Growth Factor (NGF) (Julio-Pieper et al., 2006) and Insulin Growth Factor (Schams et al., 2001) has been reported. The coordination between intraovarian factors and VEGF thus regulate follicle growth and development. In this review, the function of VEGF in ovarian functioning is summarized.


Vascular endothelial growth factor, originally termed as vascular permeability factor (VPF) was described as a 34-42 kDa protein that increases vascular permeability in the skin (Byrne et al., 2005). The VEGF family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placenta derived growth factor. Among these glycoproteins, VEGF-A is mainly involved in angiogenesis (Byrne et al., 2005). The VEGF-A exits in a five isoforms (120, 145, 164, 188 and 205) and VEGF-164 and VEGF-120 are highly expressed in mammalian ovary (Miyabayashi et al., 2006; Ng et al., 2006).

VEGF Receptor and Signaling

VEGF receptor contains an extracellular region with seven immunoglobulin-like loops and transmembrane tyrosine kinase domain (Ortega et al., 1999). Three VEGF receptors have been identified and are fms-like tyrosine kinase Flt-1 (VEGFR- 1/Flt-1), fetal liver kinase (VEGFR-2/KDR/Flk-1) and Flt-4 (VEGFR-3). Both VEGFR-1 and VEGFR-2 are expressed predominantly by vascular endothelial cells. While, VEGFR-3 is found in venous endothelium during early embryonic development, but remain confined to lymphatic endothelial cells later in fetal development (Hoeben et al., 2004; Shibuya, 2011). Although the affinity of VEGFR-2 for VEGF-A is tenfold lower than VEGFR-1 (Moghaddam et al., 2012), it is the main receptor in VEGF-induced mitogenesis and permeability (Waltenberger et al., 1994; Zachary, 1998). The VEGFR-1 plays an inhibitory role by sequestering VEGF and therefore prevents its binding with VEGFR-2 (Ferrara, 2004).

Binding of VEGF to its receptor (VEGFR-2) results in autophosphorylation of the tyrosine residues present in the domain. VEGF regulates various functions including proliferation and migration of endothelial cells, increase in vascular permeability, and cell survival by interacting with receptors and transmitting signals to various proteins (Byrne et al., 2005). Various sites for potential binding of molecules and phosphorylation have been identified but their role in VEGF stimulated response (increase vascular permeability, cell survival and regulation of angiogenesis) is unclear (Kaczmarek et al., 2005).

Physiological Regulation of VEGF in Ovarian Function


Growth and Development of Follicle

The primordial follicle is dependent on the proximity stromal vessel for uptake of nutrient and oxygen via passive diffusion as they do not have independent capillary network (Geva and Jaffe, 2000; Robinson et al., 2009). As the follicle grows, the antral follicle acquires two concentric vessels in thecal layer immediately outside the basement membrane and not penetrating the granulosa cells (Tamanini and De Ambrogi, 2004; Martelli et al., 2006). A period of rapid growth of the follicle coincides with the establishment of this vascular wreath (Geva and Jaffe, 2000). The extensive vascularization occurs due to stimulation of VEGF which might be expressed by oocyte derived factor (Robinson et al., 2009). This increased blood flow to a single follicle results in preferential delivery of gonadotropins, nutrients, oxygen and growth factors and plays necessary role in selection of follicle (Wulff et al., 2001). Also, it is observed that degeneration of capillaries in follicles is directly associated with follicular atresia (Macchiarelli et al., 1993) due to a low expression and secretion of VEGF. Similarly, inhibition of antral follicle development is observed on administration of an anti-VEGFR-2 (Zimmermann et al., 2003) indicating contribution of VEGF in follicular antrum formation (Kaczmarek et al., 2005; Ansari et al., 2017).

VEGF also has cytoprotective factor against follicular atresia by inducing expression of antiapoptotic protein in endothelial cells (Fraser et al., 2000). Follicles with high expression of VEGFR-2 exhibit low incidences of apoptosis while, the blockage of receptor inhibits the ability of cells to respond to VEGF endogenously or exogenously present and reduces protection against apoptosis (Greenaway et al., 2004).

CL Formation

VGEF appears to play an important role in growth, development and function of CL in bovines (Berisha et al., 2000; Chouhan et al., 2013). The intensive angiogenesis in the CL enable it to receive greatest amount of blood flow than any other tissue of the body (Neuvians et al., 2004). Following ovulation, reduction in local oxygen level stimulates expression of hypoxia-inducible factor (HIF-1α), a predominant stimulator for VEGF production. This HIF-1α/VEGF signaling may regulate development of CL (Wu et al., 2015). The VEGF induced hyperpermeability allows extravasation of fibrin, activation of plasminogen activators and additional growth factor to extravascular compartment for remodeling of ruptured follicle to CL (Pepper et al., 1991; Senger et al., 1993). It has been reported that about 85% of the proliferating cells in CL are derived from vascular origin (Reynolds and Redmer, 1999). Further, VEGF initiates establishment to intensive capillary network for nourishment of CL throughout its lifespan through invasion of vascular granulosa cells by endothelial cells (Kaczmarek et al., 2005).

The expression of VEGF has been found highest during early luteal phase and loss in mid phase with little expression during late luteal phase (Berisha et al., 2000; Fraser and Lunn, 2000). A decrease in VEGF expression together with dissolution of blood vessels and decline of blood flow indicate its involvement in functional and structural demise of CL (Fraser and Wulff, 2003). Further, during luteolysis, apoptosis of parenchymal cells of CL follows endothelial cells degeneration (Sawyer et al., 1990) indicate relation between regression of vasculature, functional and structural integrity of CL and VEGF expression (Berisha and Schams, 2005).

Hypoxia                                                                                  Intraovarian factors

HIF-1α                                                                                     TGF, BMP, IGF, NGF



Extensive vascularization Activation of antiapoptotic protein Extravasation of fibrin,
Activation of plasminogen
Growth factor activation

Follicular growth                     Cell survival                                  Remodeling of follicle to CL

Fig. 1: Schematic presentation of regulation of VEGF in ovarian function

Hormone Regulation

Ovarian angiogenesis is mainly regulated by luteinizing hormone (LH) (Hyder and Stancel, 1999) and LH-induced intense angiogenesis is associated with Follicle-CL transition (Dickson and Fraser, 2000). An increased VEGF expression has been reported during luteinization of granulosa cells at the time of ovulation (Yan et al., 1998; Hoeben et al., 2004). A decreased VEGF production by steroidogenic cells on treatment with GnRH antagonist is reported (Dickson and Fraser, 2000). Therefore, VEGF/VEGFR-2 pathway plays a critical role in the process follicular development mediated via. gonadotropin (Zimmermann et al., 2003). FSH stimulates expression of VEGF in granulosa cells but can influence VEGF isoform to be transcript (Shimizu et al., 2007; Ma et al., 2017). However, the mechanism regulating expression pattern of different VEGF isoforms by FSH is still unknown. Estrogen stimulates the expression of VEGF in bovine granulosa cells (Shimizu and Miyamoto, 2007) and is capable of inducing angiogenesis (Schnaper et al., 1996). Estrogen binds with specific estrogen response element present in VEGF gene and thus upregulates VEGF expression (Hyder et al., 2000) in bovine granulosa cells (Garrido et al., 1993). However, VEGF isoforms are differently expressed by the hormone. Estrogen causes upregulation of VEGF 164 expression while downregulates VEGF 120 expression in bovine granulosa cells (Shimizu & Miyamoto 2007).

Similarly, progesterone is involved in follicular angiogenesis by stimulating the expression of VEGF in granusola cells (Bailey et al., 2010). Further, the reduced luteal angiogenesis due to poor expression of VEGF has been demonstrated to result in infertility (Ebisch et al., 2008).


Ovarian follicular angiogenesis is initiated during the early stages of follicular development, and blood vessels in the thecal layer increase in number and size as the follicle develop. The strong association between angiogenesis and follicular development CL indicates critical role of VEGF in female reproduction. Several hormones and growth factors play critical role in expression of VEGF. Therefore, the study of their mechanism and interaction with each other is required for the treatment and management targeting ovarian pathology.


  1. Akiyama I, Yoshino O, Osuga Y, Shi J, Harada M, Koga K, Hirota Y, Hirata T, Fujii T, Saito S and Kozuma S. 2014. Bone Morphogenetic Protein 7 increased Vascular Endothelial Growth Factor (VEGF)-A expression in human granulosa cells and VEGF receptor expression in endothelial cells. Reproductive Sciences. 21: 477- 482.
  2. Ansari S, Patel R, Patel P, Pradhan S and Ceasar D. 2017. Molecular Mechanism of Apoptosis in Ovary. International Journal of Livestock Research. 7: 9-24.
  3. Bailey DW, Dunlap KA, Frank JW, Erikson DW, White BG, Bazer FW, Burghardt RC and Johnson GA. 2010. Effects of long-term progesterone on developmental and functional aspects of porcine uterine epithelia and vasculature: progesterone alone does not support development of uterine glands comparable to that of pregnancy. Reproduction. 140: 583–594.
  4. Berisha B and Schams D. 2005. Ovarian function in ruminants. Domestic Animal Endocrinology. 29: 305–317.
  5. Berisha B, Schams D, Kosmann M, Amselgruber W and Einspanier R. 2000. Expression and localisation of vascular endothelial growth factor and basic fibroblast growth factor during the final growth of bovine ovarian follicles. Journal of Endocrinology. 167: 371-382.
  6. Byrne AM, Bouchier-Hayes DJ and Harmey JH. 2005. Angiogenic and cell survival functions of Vascular Endothelial Growth Factor (VEGF). Journal of Cellular and Molecular Medicine. 9: 777-794.
  7. Chouhan V, Panda R, Yadav V, Babitha V, Khan F, Das GK, Gupta MDangi SSSingh GBag SSharma GTBerisha BSchams D and Sarkar M. 2013. Expression and localization of vascular endothelial growth factor and its receptors in the corpus luteum during oestrous cycle in water buffaloes (Bubalus bubalis). Reproduction in Domestic Animals. 48: 810- 818.
  8. Dickson SE and Fraser HM. 2000. Inhibition of early luteal angiogenesis by gonadotropin releasing hormone antagonist treatment in the primate. Journal of Clinical Endocrinology and 85: 2339-2344.
  9. Ebisch IMW, Thomas CMG, Wetzels AMM., Willemsen WN, Sweep FC and Steegers-Theunissen RP. 2008. Review of the role of the plasminogen activator system and vascular endothelial growth factor in subfertility.Fertility and Sterility. 90: 2340–2350.
  10. Ferrara N. 2004. Vascular endothelial growth factor: basic science and clinical progress. Endocrine Reviews. 25: 581-611.
  11. Fortune JE. 1994. Ovarian follicular growth and development in mammals. Biology of Reproduction. 50: 225–232.
  12. Fraser HM and Lunn SF. 2000. Angiogenesis and its control in the female reproductive system. British Medical Bulletin. 56: 787–797.
  13. Fraser HM and Wulff C. 2003. Angiogenesis in the corpus luteum. Reproductive Biology and Endocrinology. 1: 88.
  14. Fraser HM, Dickson SE, Lunn SF, Wulff C, Morris KD, Carroll VA and Bicknell R. 2000. Suppression of luteal angiogenesis in the primate after neutralization of vascular endothelial growth factor. 141: 995-1000.
  15. Garrido C, Saule S and Gospodarowicz D. 1993. Transcriptional regulation of vascular endothelial growth factor gene expression in ovarian bovine granulosa cells. Growth Factors. 8: 109–117.
  16. Geva E and Jaffe RB. 2000. Role of vascular endothelial growth factor in ovarian physiology and pathology. Fertility and Sterility. 74: 429–438.
  17. Greenaway J, Connor K, Pedersen HG, Coomber BL, LaMarre J and Petrik J. 2004 Vascular endothelial growth factor and its receptor, Flk-1/KDR, are cytoprotective in the extravascular compartment of the ovarian follicle. 145: 2896-2905.
  18. Hoeben A, Landuyt B, Highley MS, Wildiers H, Oosterom ATV and de Bruijn EA. 2004. Vascular Endothelial Growth Factor and Angiogenesis. Pharmacological Reviews. 56: 549–580.
  19. Hyder SM and Stancel GM. 1999. Regulation of angiogenic growth factors in the female reproductive tract by estrogens and progestins. Molecular Endocrinology. 13: 806-811.
  20. Hyder SM, Nawaz Z, Chiappetta C and Stancel GM. 2000. Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Research. 60: 3183-3190.
  21. Julio-Pieper M, Lara HE, Bravo JA, Romero C. 2006. Effects of nerve growth factor (NGF) on blood vessels area and expression of the angiogenic factors VEGF and TGF-β 1 in the rat ovary. Reproductive Biology and Endocrinology. 4: 57–67.
  22. Kaczmarek MM, Schams D and Ziecik AJ. 2005. Role of vascular endothelial growth factor in ovarian physiology – an overview. 5: 111-136.
  23. Kuo SW, Ke FC, Chang GD, Lee MT and Hwang JJ. 2011. Potential role of follicle-stimulating hormone (FSH) and transforming growth factor (TGFβ1) in the regulation of ovarian angiogenesis. Journal of Cellular Physiology. 226: 1608-1619.
  24. Ma WZ, Zheng XM, Hei CC, Zhao Cj, Xie SS, Chang Q, Cai YF, Jia H, Pei XY and Wang YR. 2017. Optimal FSH usage in revascularization of allotransplanted ovarian tissue in mice. Journal of Ovarian Research. 10: 1-10.
  25. Macchiarelli G, Nottola SA, Vizza E, Familiari G, Kikuta A, Murakami T and Motta PM. 1993. Microvasculature of growing and atretic follicles in the rabbit ovary: a SEM study of corrosion casts. Archives of Histology and Cytology. 56: 1-12.
  26. Martelli A, Berardinelli P, Russo V, Mauro A, Bernabo N, Gioia L, Mattioli M and Barboni B. 2006. Spatio-temporal analysis of vascular endothelial growth factor expression and blood vessel remodelling in pig ovarian follicles during the periovulatory period. Journal of Molecular Endocrinology. 36: 107-119.
  27. Miyabayashi K, Shimizu T, Kawauchi C, Sasada H and Sato E. 2005. Changes of mRNA expression of vascular endothelial growth factor (VEGF), angiopoietins and their specific receptors during the periovulatory phase in eCG/hCG-primed immature female rats. Journal of Experimental Part A. 303: 590–597.

28.              Moghaddam SS, Amini A, Moris DL and Pourgholami MH. 2012. Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer. Cancer and Metastatic Reviews. 31: 143-162.

  1. Neuvians TP, Berisha B and Schams D. 2004. VEGF and FGF expression during induced luteolysis in the bovine corpus luteum. Molecular Reproduction and Development. 67: 389-395.
  2. Ng YS, Krilleke D and Shima DT. 2006. VEGF functions in vascular pathogenesis. Experimaental Cell Research. 312: 527-537.
  3. Ortega N, Hutchings H and Plouet J. 1999. Signal relays in the VEGF system. Frontiers in Bioscience. 4: 141-152
  4. Pepper MS, Ferrara N, Orci L and Montesano R. 1991. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochemical and Biophysical Research Communications. 181: 902-906.
  5. Reynolds LP and Redmer DA. 1999. Growth and development of the corpus luteum. Journal of Reproduction and Fertility. Supplement. 54: 181–191.
  6. Robinson RSWoad KJHammond AJLaird MHunter MG and Mann GE. 2009. Angiogenesis and vascular function in the ovary. 138: 869-81.
  7. Sawyer HR, Niswender KD, Braden TD and Niswender GD. 1990. Nuclear changes in ovine luteal cells in response to PGF2α. Domestic Animal Endocrinology 229- 237.
  8. Schams D, Kosmann M, Berisha B, Amselgruber WM and Miyamoto A. 2001. Stimulatory and synergistic effects of luteinising hormone and insulin like growth factor 1 on the secretion of vascular endothelial growth factor and progesterone of cultured bovine granulosa cells. Experimental and Clinical Endocrinology & Diabetes.109: 155–62.

37.              Schnaper HW, McGowan KA, Kim-Schulze S and Cid MC. 1996. Oestrogen and endothelial cell angiogenic activity. Clinical and Experimental Pharmacology and Physiology. 23: 247- 250.

  1. Senger DR, Van de Water L, Brown LF, Nagy JA, Yeo KT, Yeo TK, Berse B, Jackman RW, Dvorak AM and Dvorak HF. 1993 Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer and Metastasis Reviews. 12: 303-324.
  2. Shibuya M. 2011.Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: A Ccucial target for anti- and pro-angiogenic therapies. Genes and Cancer 2: 1097–1105.
  3. Shimizu T and Miyamoto A. 2008. Progesterone induces the expression of vascular endothelial growth factor (VEGF) 120 and F1k-1, its receptor, in bovine granulosa cells Animal Reproduction Science. 102: 228-37.
  4. Shimizu T, Jayawardana BC, Tetsuka M and Miyamoto A. 2007. Differential effect of follicle-stimulating hormone and estradiol on expressions of vascular endothelial growth factor (VEGF) 120, VEGF164 and their receptors in bovine granulosa cells. Journal of Reproduction and Development. 53: 105-112.
  5. Tamanini C and Ambrogi2004. Angiogenesis in developing follicle and corpus luteum. Reproduction in Domestic Animal. 39:206–16.
  6. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M and Heldin CH. 1994. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. The Journal of Biological Chemistry. 269: 26988–26995.
  7. Wu L, Zhenghong Z, Xiaoyan P and Wang Z. 2015. Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats. Molecular Medicine Reports. 12: 7153-7159.
  8. Wulff C, Dickson SE, Duncan WC and Fraser HM. 2001. Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Human Reproduction. 16: 2515-2524.
  9. Yan Z, Neulen J, Raczek S, Weich HA, Keck C, Grunwald K and Breckwoldt M. 1998. Secretion of vascular endothelial growth factor (VEGF) permeability factor (VPF) production by luteinized human granulosa cells in vitro; a paracrine signal in corpus luteum formation. Gynecological 12: 149-153.
  10. Zachary I. 1998. Vascular endothelial growth factor: how it transmits its signal. Experimental Nephrology. 6: 480–487.
  11. Zimmermann RC, Hartman T, Kavic S, Pauli SA, Bohlen P, Sauer MV and Kitajewski J. 2003. Vascular endothelial growth factor receptor 2-mediated angiogenesis is essential for gonadotropin-dependent follicle development. Journal of Clinical Investigation. 112: 659-669.
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