Objectives:To study serum levels of vascular endothelial growth factor (VEGF), a potent angiogenic factor, during distinct periods of the female life span and compare them with corresponding levels of age-matched males. It is hypothesized that VEGF might be increased at periods of enhanced angiogenesis.
Methods:Venous blood was drawn from healthy females (n = 59) and males (n = 53) divided into six groups: fetuses (cord blood), neonates, children, adults (same females in the proliferative and secretory phases of their menstrual cycle), pregnant, and elderly (postmenopausal). Serum VEGF levels were measured by an enzyme immunoassay.
Results:Females showed 49% higher serum VEGF levels than males (t = 2.74, P = .01). Cord and neonatal blood levels were significantly increased compared with those of adults (t = 2.41, P = .02, and t = 5.81, P = .0001, respectively). All female age groups presented higher serum VEGF levles than the group of women in the proliferative phase of the cycle; nevertheless, VEGF levels in the secretory phase did not differ (t = 1.85, P = .07).
Conclusions:Serum VEGF levels are higher in females than in males and during life periods characterized by enhanced growth and development, implying increased rates of angiogenesis.
1. Folkman J, Shing Y. Angiogenesis. J Biol Chem1992;267:10931-10934.
2.
2. Gordon JD, Shifren JL, Foulk RA, Taylor RN, Jaffe RB. Angiogenesis in the human female reproductive tract. Obstet Gynecol Surv1995;50:688-697.
3.
3. Folkman J. Clinical applications of research on angiogenesis. N Engl J Med1995;333:1757-1763.
4.
4. Ferrara N, Heipsobn H, Walder CE, Bunting S, Thomas GR. The regulation of blood vessel growth by vascular endothelial growth factor. Ann N Y Acad Sci1995;752:246-256.
5.
5. Ferrara N, Carver-Moore K, Chen H. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature1996;380:439-442.
6.
6. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: Identification of a fourth molecular species and characterization of alternative splicting of RNA. Mol Endocrinol1991;5:1806-1814.
7.
7. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC. The human gene for vascular endothelial growth factor: Multiple protein forms are encoded through alternative exon splicing. J Biol Chem1991;266:11947-11954.
8.
8. Thomas KA. Vascular endothelial growth factor, a potent and selective angiogenic agent. J Biol Chem1991;271:603-606.
9.
9. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem1992;267:26031-26037.
10.
10. Malamitsi-Puchner A, Sarandakou A, Giannaki G, Rizos D, Phocas I. Changes of angiogenin serum concentrations in the perinatal period. Pediatr Res1997;41:909-911.
11.
11. Malamitsi-Puchner A, Tziotis J, Protonotariou E, Sarandakou A, Creatsas G. Heparin-binding angiogenic factors (basic fibroblast growth factor and vascular endothelial growth factor) in early neonatal life. Pediatr Res1999;45:877-880.
12.
12. Charnock-Jones DS, Clark DE, He YL. Placental production of a locally and systematically acting soluble factor which inhibits vascular endothelial growth factor (VEGF). J Sog Gynecol Invest1997;4 (suppl), abstr 438-438.
13.
13. Hornig C, Barleon B, Ahmad S, Vuorela P, Ahmed A, Weich HA. Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids. Lab Invest2000;80:443-454.
14.
14. Folkman J, Klagsbrun M. Angiogenic factors. Science1987;235:442-447.
15.
15. Cullinan-Bove K, Koos R. Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: Rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology1993;133:829-837.
16.
16. Hyder SM, Stancel GM, Chiappeta C. Uterine expression of vascular endothelial growth factor is increased by estradiol and tamoxifen. Cancer Res1996;56:3954-3960.
17.
17. Torry DS, Torry RJ. Angiogenesis and the expression of vascular endothelial growth factor in endometrium and placenta. Am J Reprod Immunol1997;37:21-29.
18.
18. Greb RR, Heikinheimo O, Williams RF, Hodgen GD, Goodman AL. Vascular endothelial growth factor in primate endometrium is regulated by estrogen-receptor and progesterone receptor ligands in vivo. Hum Reprod1997;12:1280-1292.
19.
19. Sharkey AM, Charnock-Jones DS, Boocock CA, Brown KD, Smith SK. Expression of mRNA for vascular endothelial growth factor in human placenta. J Reprod Fertil1993;99:609-615.
20.
20. Berse B, Brown LF, Van De Water L, Dvorak HF, Senger DR. Vascular permeability factor (VEGF) gene is expressed differentially in normal tissues, macrophages and tumors. Mol Biol Cell1992;3:211-220.
21.
21. Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev1992;13:18-32.
22.
22. Carr BR, MacDonald PC, Simpson ER. The role of lipoproteins in the regulation of progesterone secretion by the human corpus leteum. Fertil Steril1982;38:303-311.
23.
23. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol1992;24:471-476.
24.
24. Rusnati M, Casarotti G, Pecorelli S, Ragnotti G, Presta M. Basic fibroblast growth factor in ovulatory cycle and postmenopausal human endometrium. Growth Factors1990;3:299-307.
25.
25. Malamitsi-Puchner A, Tziotis J, Tsonou A, Protonotariou E, Sarandakou A, Cretsas G. Basic fibroblast growth factor: Serum levels in the female. Growth Factors1999;17:215-220.
26.
26. Baker PN, Krasnow J, Roberts JM, Yeo KT. Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol1992;86:815-821.
27.
27. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A1993;90:10705-10709.
