Plasma markers of angiogenesis in pregnancy induced hypertension

Sunil K. Nadar; Ioannis Karalis; Eman Al Yemeni; Andrew D. Blann; Gregory Y. H. Lip

doi:10.1160/TH05-03-0167

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(05): 1071-1076
DOI: 10.1160/TH05-03-0167

Endothelium and Vascular Development

Schattauer GmbH

Plasma markers of angiogenesis in pregnancy induced hypertension

Authors

Sunil K. Nadar

¹Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
Ioannis Karalis

¹Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
Eman Al Yemeni

¹Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
Andrew D. Blann

¹Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
Gregory Y. H. Lip

¹Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK

Abstract

Summary

This study tests the hypothesis that abnormalities in plasma indices of angiogenesis, such as Vascular Endothelial Growth Factor (VEGF) and angiopoietins (Ang-1, Ang-2), as well as their soluble receptors Flt-1 (sflt-1) and Tie 2 (sTie-2) respectively, are present in women with in pregnancy-induced hypertension (PIH). We also measured platelet levels of VEGF and Ang-1 (pVEGF and pAng-1 respectively). We studied 69 consecutive women with PIH (34 without proteinuria, and 35 with proteinuria, i.e. preeclampsia) who were compared to 64 consecutive women with normotensive pregnancies and 30 normotensive non-pregnant women, in a cross-sectional study. Using ELISA, we measured levels of plasma VEGF, Ang-1 &2, Tie-2 and sflt-1, and also the levels of angiogenic markers within the platelet [platelet VEGF (pVEGF) and platelet Ang-1 (pAng1)] by lysing a fixed number of platelets with 0.5% tween. Results show that levels of plasma VEGF, Ang-1, Ang2, sFlt-1 and Tie-2 were significantly different between the study groups. Post hoc analyses revealed plasma Ang-1 was highest in the preeclampsia group (p<0.001), whilst Ang-2 was highest in the normotensive pregnant group (p-=0.018). Plasma Tie-2 was highest in the PIH group. VEGF levels were significantly different between the preeclampsia group and the PIH group (p<0.05). Platelet VEGF levels were higher in the non-pregnant group than in the pregnant group, but there were no significant differences in the platelet levels of Ang-1 between the different groups. Ang-2, sFlt-1 and Tie-2 were undetectable in the platelet lysate in any of the patient groups or controls. Blood pressure was a major determinant of the different angiogenic factors studied. Abnormal indices of angiogenesis are evident in PIH and preeclampsia, with higher levels of sFlt-1 and lower levels ofVEGF; in PIH, increased levels of Ang-1 and Tie-2, but reduced Ang-2, are evident compared to normal pregnancy. These abnormalities may have implications for the pathogenesis of PIH and preeclampsia.

Keywords

Pregnancy induced hypertension - preeclampsia - vascular endothelial growth factor - angiopoietin-1 - angiopoietin-2 - angiogenesis

Full Text

References

References
1 Meis PJ, Goldenberg RL, Mercer BM. The preterm prediction study: risk factors for indicated preterm births. Am J Obstet Gynecol 1998; 178: 562-7.
2 Roberts J, Cooper D. Pathogenesis and genetics of pre-eclampsia. Lancet 2001; 357: 53-6.
3 Pijnenborg R, Anthony J, Davey DA. et al. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynecol 1991; 98: 648-55.
4 Roberts JM. Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol 1998; 16: 5-15.
5 Maynard SE, Min JY, Merchan J. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt-1) may contribute to endothelial dysfunction, hypertension and proteinuria in preeclampsia. J Clin Investig 2003; 111: 649-58.
6 Luttun A, Carmeliet P. Soluble VEGF receptor Flt-1: the elusive preeclampsia factor discovered?. J Clin Invest 2003; 111: 600-2.
7 Vuorela P, Lintula S, Stenman UH. et al. Expression of vascular endothelial growth factor in peripheral blood cells of preeclamptic women. Hypertens Pregnancy 2003; 22: 193-201.
8 Dunk C, Shams M, Nijjar S. et al. Angiopoietin-1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development. Am J Pathol 2000; 156: 2185-99.
9 Zhang EG, Smith SK, Baker PN. et al. The regulation and localization of angiopoietin-1, –2, and their receptor Tie2 in normal and pathologic human placentae. Mol Med 2001; 7: 624-35.
10 Maisonpierre PC, Suri C, Jones PF. et al. Angiopoietin- 2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277: 55-60.
11 Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci U S A 2002; 99: 11205-10.
12 Zhou Y, Bellingard V, Feng KT. et al. Human cytotrophoblasts promote endothelial survival and vascular remodeling through secretion of Ang2, PlGF, and VEGF-C. Dev Biol 2003; 263: 114-25.
13 Geva E, Ginzinger DG, Zaloudek CJ. et al. Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J Clin Endocrinol Metab 2002; 87: 4213-24.
14 Shalaby F, Rossant J, Yamaguchi TP. et al. Failure of blood-island formation and vasculogenesis in Flk- 1-deficient mice. Nature 1995; 376: 62-6.
15 Jones N, Iljin K, Dumont DJ. et al. Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2001; 2: 257-67.
16 Davis S, Aldrich TH, Jones PF. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 1996; 87: 1161-9.
17 Leach L, Babawale MO, Anderson M. et al. Vasculogenesis, angiogenesis and the molecular organisation of endothelial junctions in the early human placenta. J Vasc Res 2002; 39: 246-59.
18 Wulff C, Wilson H, Dickson SE. et al. Hemochorial placentation in the primate: expression of vascular endothelial growth factor, angiopoietins, and their receptors throughout pregnancy. Biol Reprod 2002; 66: 802-12.
19 Regnault TR, Galan HL, Parker TA. et al. Placental development in normal and compromised pregnancies– a review. Placenta 2002; 23 A S119-S129.
20 Chung NA, Makin AJ, Lip GY. Measurement of the soluble angiopoietin receptor tie-2 in patients with coronary artery disease: development and application of an immunoassay. Eur J Clin Invest 2003; 33: 529-35.
21 Caine GJ, Blann AD, Stonelake PS. et al. Plasma angiopoietin- 1, angiopoietin-2 and Tie-2 in breast and prostate cancer: a comparison with VEGF and Flt-1. Eur J Clin Invest 2003; 33: 883-90.
22 Chong AY, Caine GJ, Freestone B. et al. Plasma angiopoietin- 1, angiopoietin-2, and angiopoietin receptor tie-2 levels in congestive heart failure. J Am Coll Cardiol 2004; 43: 423-8.
23 Belgore FM, Blann AD, Lip GY. Measurement of free and complexed soluble vascular endothelial growth factor receptor, Flt-1, in fluid samples: development and application of two new immunoassays. Clin Sci 2001; 100: 567-75.
24 Kamath S, Blann AD, Caine GJ. et al. Platelet P-selectin levels in relation to plasma soluble P-selectin and beta-thromboglobulin levels in atrial fibrillation. Stroke 2002; 33: 1237-42.
25 Levine RJ, Maynard SE, Qian C. et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672-83.
26 Livingston JC, Chin R, Haddad B. et al. Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol 2000; 183: 1554-7.
27 Polliotti BM, Fry AG, Saller DN. et al. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol 2003; 101: 1266-74.
28 Hornig C, Barleon B, Ahmad S. et al. Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids. Lab Invest 2000; 80: 443-54.
29 Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 1999; 13: 1055-66.
30 Zhou Y, McMaster M, Woo K. et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 2002; 160: 1405-23.
31 Distler JH, Hirth A, Kurowska-Stolarska M. et al. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 2003; 47: 149-61.
32 Chong AY, Caine GJ, Lip GY. Angiopoietin/tie-2 as mediators of angiogenesis: a role in congestive heart failure?. Eur J Clin Invest 2004; 34: 9-13.
33 Tidwell SC, Ho HN, Chiu WH. et al. Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol 2001; 184: 1267-72.
34 Su YN, Lee CN, Cheng WF. et al. Decreased maternal serum placenta growth factor in early second trimester and preeclampsia. Obstet Gynecol 2001; 97: 898-904.
35 Persico MG, Vincenti V, DiPalma T. Structure, expression and receptor-binding properties of placenta growth factor (PlGF). Curr Top Microbiol Immunol 1999; 237: 31-40.
36 Livingston JC, Haddad B, Gorski LA. et al. Placenta growth factor is not an early marker for the development of severe preeclampsia. Am J Obstet Gynecol 2001; 184: 1218-20.
37 Torry DS, Ahn H, Barnes EL. et al. Placenta growth factor: potential role in pregnancy. Am J Reprod Immunol 1999; 41: 79-85.
38 De Falco S, Gigante B, Persico MG. Structure and function of placental growth factor. Trends Cardiovasc Med 2002; 12: 241-6