Disruption of components of vascular endothelial growth factor angiogenic signalling system in metabolic syndrome

Summary

Metabolic syndrome (MetS) is associated with impaired angiogenesis, a process that is chiefly regulated by vascular endothelial growth factor (VEGF) upon binding to its specific receptors, VEGF-R1 and VEGF-R2. The purpose of the present study was to assess trends or patterns in plasma levels of VEGF and its soluble receptors in subjects with (MetS) or without (non-MetS) MetS; and further examine their association with clinical or metabolic parameters using a subpopu-lation of South Asian country. A total of 1,802 rural Bangladeshi women aged ≥15 years were studied using a population-based cross-sectional survey. Plasma levels of VEGF were found to be significantly increased (MetS vs. non-MetS: 483.9 vs. 386.9, p<0.001), whereas, the soluble forms of VEGF receptors, sVEGF-R1 and sVEGF-R2, were significantly decreased in subjects with Mets (sVEGF-R1, MetS vs. non-MetS: 512.5 vs. 631.3, p<0.001; sVEGF-R2, MetS vs. non-MetS: 9,302.8 vs. 9,787.4, p=0.004). After adjustment for age and all potential variables, multiple regression analysis revealed that plasma levels of VEGF had significant positive association with blood glucose (p = 0.019) and body mass index (p = 0.007). We also found that mean plasma levels of VEGF increased in direct proportion to levels of MetS components. The present study is the first ever to demonstrate a positive association between trends in levels of plasma VEGF and MetS using a large sample size from South Asia. The association between plasma VEGF and MetS needs further investigations in order to clearly decipher the clinical predictive value and accuracy of plasma VEGF in MetS.

Keywords

Metabolic syndrome - vascular endothelial growth factor - rural Bangladeshi women - South Asian

• References

• 1 Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab 2007; 92: 399-404.
• 2 Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome: prevalence in worldwide populations. Endocrinol Metab Clin North Am 2004; 33: 351-375.
• 3 Eckel RH, Alberti KG, Grundy SM. et al. The metabolic syndrome. Lancet 2010; 375: 181-183.
• 4 Schiekofer S, Galasso G, Sato K. et al. Impaired revascularisation in a mouse model of type 2 diabetes is associated with dysregulation of a complex angio-genic-regulatory network. Arterioscler Thromb Vasc Biol 2005; 25: 1603-1609.
• 5 Yilmaz MB, Biyikoglu SF, Akin Y. et al. Obesity is associated with impaired coronary collateral vessel development. Int J Obes Relat Metab Disord 2003; 27: 1541-1545.
• 6 Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab 2008; 93 (Suppl. 01) S9-30.
• 7 Sheth T, Nair C, Nargundkar M. et al. Cardiovascular and cancer mortality among Canadians of European, south Asian and Chinese origin from 1979 to 1993: an analysis of 1.2 million deaths. CMAJ 1999; 161: 132-138.
• 8 King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care 1998; 21: 1414-1431.
• 9 Anand SS, Yusuf S, Vuksan V. et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet 2000; 356: 279-284.
• 10 Neufeld G, Cohen T, Gengrinovitch S. et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13: 9-22.
• 11 Shibuya M. Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). Int J Biochem Cell Biol 2001; 33: 409-420.
• 12 Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol 2006; 39: 469-478.
• 13 Swendeman S, Mendelson K, Weskamp G. et al. VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signalling. Circ Res 2008; 103: 916-918.
• 14 Ebos JM, Bocci G, Man S. et al. A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol Cancer Res 2004; 02: 315-326.
• 15 Kou B, Li Y, Zhang L. et al. In vivo inhibition of tumor angiogenesis by a soluble VEGFR-2 fragment. Exp Mol Pathol 2004; 76: 129-137.
• 16 Jacobi J, Tam BY, Wu G. et al. Adenoviral gene transfer with soluble vascular endothelial growth factor receptors impairs angiogenesis and perfusion in a murine model of hindlimb ischemia. Circulation 2004; 110: 2424-2429.
• 17 Szentirmai O, Baker CH, Bullain S. et al. Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor re-ceptor-2: laboratory investigation. J Neurosurg 2008; 108: 979-988.
• 18 Tsatsaris V, Goffin F, Foidart JM. et al. Circulating angiogenic factors and pre-eclampsia. N Engl J Med. 2004 350. 2003-2004; author reply 2003-2004.
• 19 Munaut C, Lorquet S, Pequeux C. et al. Hypoxia is responsible for soluble vascular endothelial growth factor receptor-1 (VEGFR-1) but not for soluble endoglin induction in villous trophoblast. Hum Reprod 2008; 23: 1407-1415.
• 20 Robak E, Sysa-Jedrzejewska A, Robak T. Vascular endothelial growth factor and its soluble receptors VEGFR-1 and VEGFR-2 in the serum of patients with systemic lupus erythematosus. Mediators Inflamm 2003; 12: 293-298.
• 21 Naumnik W, Izycki T, Swidzin’ska E. et al. Serum levels of VEGF-C, VEGF-D, and sVEGF-R2 in patients with lung cancer during chemotherapy. Oncol Res 2007; 16: 445-451.
• 22 Kearney JB, Kappas NC, Ellerstrom C. et al. The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood 2004; 103: 4527-4535.
• 23 Kappas NC, Zeng G, Chappell JC. et al. The VEGF receptor Flt-1 spatially modulates Flk-1 signalling and blood vessel branching. J Cell Biol 2008; 181: 847-858.
• 24 Chappell JC, Taylor SM, Ferrara N. et al. Local guidance of emerging vessel sprouts requires soluble Flt-1. Dev Cell 2009; 17: 377-386.
• 25 World Bank: World Development Indicator. USA: World Bank. http://data.worldbank.org/country/bangladesh
• 26 The world fact book. www.cia.gov/library/publications/the-world-fact">http:www.cia.gov/library/publications/the-world-factbook/fields/2046.html">www.cia.gov/library/publications/the-world-factbook/fields/2046.html
• 27 Jesmin S, Islam MR, Islam AM. et al. Comprehensive assessment of metabolic syndrome among rural Bangladeshi women. BMC Public Health 2012; 12: 49.
• 27 Schaper W, De Brabander M, Lewi P. DNA synthesis and mitoses in coronary collateral vessels of the dog. Circ Res 1971; 28: 671-679.
• 28 Wright HP. Endothelial mitosis around aortic branches in normal guinea pigs. Nature 1968; 220: 78-79.
• 29 Spaet TH, Lejnicks I. Mitotic activity of rabbit blood vessels. Proc Soc Exp Biol Med 1967; 125: 1197-1201.
• 30 Leblond CP. Classification of cell populations on the basis of their proliferative behavior. Nat Cancer Inst Monogr 1964; 14: 119-150.
• 31 Lieb W, Safa R, Benjamin EJ. et al. Vascular endothelial growth factor, its soluble receptor, and hepatocyte growth factor: clinical and genetic correlates and association with vascular function. Eur Heart J 2009; 30: 1121-1127.
• 32 Siervo M, Ruggiero D, Sorice R. et al. Angiogenesis and biomarkers of cardiovascular risk in adults with metabolic syndrome. J Intern Med 2010; 268: 338-347.
• 33 Sandhofer A, Tatarczyk T, Kirchmair R. et al. Are plasma VEGF and its soluble receptor sFlt-1 atherogenic risk factors? Cross-sectional data from the SAPHIR study. Atherosclerosis 2009; 206: 265-269.
• 34 Felmeden DC, Spencer CG, Belgore FM. et al. Endothelial damage and angiogenesis in hypertensive patients: relationship to cardiovascular risk factors and risk factor management. Am J Hypertens 2003; 16: 11-20.
• 35 Jesmin S, Mia S, Islam AM. et al. Prevalence of metabolic syndrome among rural Bangladeshi women. Diabetes Res Clin Prac 2012; 95: e7-9.
• 36 Silha JV, Krsek M, Sucharda P. et al. Angiogenic factors are elevated in overweight and obese individuals. Int J Obes 2005; 29: 1308-1314.
• 37 Miyazawa-Hoshimoto S, Takahashi K, Bujo H. et al. Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia 2003; 46: 1483-1488.
• 38 Wada H, Satoh N, Kitaoka S. et al. Soluble VEGF receptor-2 is increased in sera of subjects with metabolic syndrome in association with insulin resistance. Atherosclerosis 2010; 208: 512-517.
• 39 Siervo M, Ruggiero D, Sorice R. et al. Body mass index is directly associated with biomarkers of angiogenesis and inflammation in children and adolescents. Nutrition 2012; 28: 262-266.
• 40 Blann AD, Belgore FM, McCollum CN. et al. Vascular endothelial growth factor and its receptor, Flt-1, in the plasma of patients with coronary or peripheral atherosclerosis, or Type II diabetes. Clin Sci 2002; 102: 187-194.
• 41 Kim SY, Lee SH, Park S. et al. Vascular endothelial growth factor, soluble fms-like tyrosine kinase 1, and the severity of coronary artery disease. Angiology 2011; 62: 176-183.
• 42 Guo Q, Carrero JJ, Yu X. et al. Associations of VEGF and its receptors sVEGFR-1 and −2 with cardiovascular disease and survival in prevalent haemo-dialysis patients. Nephrol Dial Transplant 2009; 24: 3468-3473.
• 43 Shibuya M, Yamaguchi S, Yamane A. et al. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 1990; 05: 519-524.
• 44 Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 1993; 90: 10705-10709.