Low pericyte coverage of endometrial microvessels in heavy menstrual bleeding correlates with the microvessel expression of VEGF-A

Andersson,Emil; Zetterberg,Eva; Vedin,Inger; Hultenby,Kjell; Palmblad,Jan; Mints,Miriam

doi:10.3892/ijmm.2014.2035

Low pericyte coverage of endometrial microvessels in heavy menstrual bleeding correlates with the microvessel expression of VEGF-A

Authors:
- Emil Andersson
- Eva Zetterberg
- Inger Vedin
- Kjell Hultenby
- Jan Palmblad
- Miriam Mints
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Affiliations: Department of Women's and Children's Health, Karolinska Institutet at Karolinska University Hospital Solna, S-17176 Stockholm, Sweden, Departments of Medicine and Hematology, Karolinska Institutet and Karolinska University Hospital Huddinge, S-14186 Stockholm, Sweden, Department of Coagulation, Skånes University Hospital, S-21428 Malmö, Sweden, Department of Laboratory Medicine, Karolinska Institutet, S-14186 Stockholm, Sweden
Published online on: December 11, 2014 https://doi.org/10.3892/ijmm.2014.2035
Pages: 433-438

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Abstract

A prospective clinical study was carried out to investigate whether endometrial microvessels in patients with idiopathic heavy menstrual bleeding (HMB) of endometrial origin (HMB-E) are fragile due to low pericyte coverage. Idiopathic HMB-E is characterized by large endothelial cell gaps related to the microvascular overexpression of vascular endothelial growth factor (VEGF)-A and VEGF receptors 1-3. A total of 10 women with a normal menstrual cycle and a history of HMB of <5 years, and 17 healthy women with a normal menstrual cycle were recruited from the Karolinska University Hospital. Blood samples were obtained for hormone analysis and coagulation tests. Endometrial biopsies were collected in the proliferative or in the secretory phase. Pericyte coverage was assessed using immunohistochemical staining for smooth muscle actin-α (SMAα) and by image analysis (microvascular density) of endometrial biopsies from 10 patients with HMB-E and 17 healthy ovulating women (control subjects). Previously published data on endothelial cell gap size and the expression of VEGF receptors were used. Although microvascular density did not differ between the patients with HMB-E and the control subjects, the number of SMAα-positive microvessels in the proliferative phase was significantly (P=0.005) lower in the patients with HMB-E than in the control subjects. Moreover, the number of SMAα-positive microvessels in the control subjects was significantly fewer in the secretory (P=0.04) than in the proliferative phase, whereas this number did not differ among the patients with HMB-E regardless of phase. A significant negative correlation was observed between the number of VEGF-A-positive microvessels and microvessels with pericyte coverage (r=0.8; P=0.04). Finally, the endothelial cell layer was significantly thicker in the patients with HMB-E than in the control subjects. Thus, the upregulation of VEGF-A in idiopathic HMB-E is associated with a low pericyte coverage during the proliferative phase of intense angiogenesis, which may confer vessel fragility, possibly leading to excessive blood loss.

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1	Hallberg L, Högdahl AM, Nilsson L and Rybo G: Menstrual blood loss - a population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand. 45:320–351. 1966. View Article : Google Scholar
2	Gath D, Osborn M, Bungay G, Iles S, Day A, Bond A and Passingham C: Psychiatric disorder and gynaecological symptoms in middle aged women: a community survey. Br Med J (Clin Res Ed). 294:213–218. 1987. View Article : Google Scholar
3	Salamonsen LA, Kovacs GT and Findlay JK: Current concepts of the mechanisms of menstruation. Baillieres Best Pract Res Clin Obstet Gynaecol. 13:161–179. 1999. View Article : Google Scholar
4	Mints M, Blomgren B and Palmblad J: Expression of vascular endothelial growth factor receptor-3 in the endometrium in menorrhagia. Int J Mol Med. 19:909–913. 2007.PubMed/NCBI
5	Mints M, Blomgren B and Palmblad J: Expression of angiopoietins 1, 2 and their common receptor tie-2 in relation to the size of endothelial lining gaps and expression of VEGF and VEGF receptors in idiopathic menorrhagia. Fertil Steril. 94:701–707. 2010. View Article : Google Scholar
6	Mints M, Hultenby K, Zetterberg E, Blomgren B, Falconer C, Rogers R and Palmblad J: Wall discontinuities and increased expression of vascular endothelial growth factor-A and vascular endothelial growth factor receptors 1 and 2 in endometrial blood vessels of women with menorrhagia. Fertil Steril. 88:691–697. 2007. View Article : Google Scholar : PubMed/NCBI
7	Gerhardt H and Betsholtz C: Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 314:15–23. 2003. View Article : Google Scholar : PubMed/NCBI
8	Hellström M, Kalén M, Lindahl P, Abramsson A and Betsholtz C: Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development. 126:3047–3055. 1999.PubMed/NCBI
9	Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E and Betsholtz C: Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 8:1875–1887. 1994. View Article : Google Scholar : PubMed/NCBI
10	Hirschi KK and D’Amore PA: Pericytes in the microvasculature. Cardiovasc Res. 32:687–698. 1996. View Article : Google Scholar : PubMed/NCBI
11	Hellström M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H and Betsholtz C: Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol. 153:543–553. 2001. View Article : Google Scholar : PubMed/NCBI
12	Hewett P, Nijjar S, Shams M, Morgan S, Gupta J and Ahmed A: Down-regulation of angiopoietin-1 expression in menorrhagia. Am J Pathol. 160:773–780. 2002. View Article : Google Scholar : PubMed/NCBI
13	Higham JM, O’Brien PM and Shaw RW: Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 97:734–739. 1990. View Article : Google Scholar : PubMed/NCBI
14	Mints M, Blomgren B, Falconer C, Fianu-Jonasson A and Palmblad J: Microvascular density, vascular endothelial growth factor A, and its receptors in endometrial blood vessels in patients with menorrhagia. Fertil Steril. 84:692–700. 2005. View Article : Google Scholar : PubMed/NCBI
15	Zetterberg E, Vannucchi AM, Migliaccio AR, Vainchenker W, Tulliez M, Dickie R, Hasselbalch H, Rogers R and Palmblad J: Pericyte coverage of abnormal blood vessels in myelofibrotic bone marrows. Haematologica. 92:597–604. 2007. View Article : Google Scholar : PubMed/NCBI
16	Förster C1, Mäkela S, Wärri A, Kietz S, Becker D, Hultenby K, Warner M and Gustafsson JA: Involvement of estrogen receptor beta in terminal differentiation of mammary gland epithelium. Proc Natl Acad Sci USA. 99:15578–15583. 2002. View Article : Google Scholar : PubMed/NCBI
17	Weibel E: Stereological Methods: Practical methods for biological morphometry. Academic Press; London: 1979
18	Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD and McDonald DM: Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 116:2610–2621. 2006. View Article : Google Scholar : PubMed/NCBI
19	Dulmovits BM and Herman IM: Microvascular remodeling and wound healing: a role for pericytes. Int J Biochem Cell Biol. 44:1800–1812. 2012. View Article : Google Scholar : PubMed/NCBI
20	Goddard LM and Iruela-Arispe ML: Cellular and molecular regulation of vascular permeability. Thromb Haemost. 109:407–415. 2013. View Article : Google Scholar : PubMed/NCBI
21	Sims DE and Westfall JA: Analysis of relationships between pericytes and gas exchange capillaries in neonatal and mature bovine lungs. Microvasc Res. 25:333–342. 1983. View Article : Google Scholar : PubMed/NCBI
22	Girling JE and Rogers PA: Recent advances in endometrial angiogenesis research. Angiogenesis. 8:89–99. 2005. View Article : Google Scholar : PubMed/NCBI
23	Girling JE, Lederman FL, Walter LM and Rogers PA: Progesterone, but not estrogen, stimulates vessel maturation in the mouse endometrium. Endocrinology. 148:5433–5441. 2007. View Article : Google Scholar : PubMed/NCBI
24	Girling JE and Rogers PA: Regulation of endometrial vascular remodelling: role of the vascular endothelial growth factor family and the angiopoietin-TIE signalling system. Reproduction. 138:883–893. 2009. View Article : Google Scholar : PubMed/NCBI
25	Rogers PA, Plunkett D and Affandi B: Perivascular smooth muscle alphaactin is reduced in the endometrium of women with progestin-only contraceptive breakthrough bleeding. Hum Reprod. 15(Suppl 3): S78–S84. 2000. View Article : Google Scholar
26	Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N and Cheresh DA: A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature. 456:809–813. 2008. View Article : Google Scholar : PubMed/NCBI