Placenta
Volume 29, Supplement , Pages 48-54, March 2008

Endometrial Lymphangiogensis

  • P.A.W. Rogers

      Affiliations

    • Corresponding Author InformationCorresponding author at: Centre for Women's Health Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Tel.: +61 03 9594 5389; fax: +61 03 9594 6389.
    • ,
  • J.F. Donoghue
    • ,
  • J.E. Girling

Centre for Women's Health Research, Monash University Department of Obstetrics and Gynaecology and Monash Institute for Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia

Accepted 26 September 2007. published online 05 November 2007.

Article Outline

Abstract 

This article briefly summarises some of the more important recent advances in understanding of lymphangiogenesis, and then reviews current knowledge of the lymphatics and lymphangiogenesis in the endometrium. The recent identification of vascular endothelial growth factor-C (VEGF-C) and VEGF-D, as well as specific lymphatic endothelial cell (LEC) markers such as vascular endothelial growth factor receptor-3 (VEGF-R3), lymphatic endothelial hyaluronan receptor-1 (LYVE-1), podoplanin, and prospero-related homeobox-1 (PROX1), has provided the tools to characterize and investigate lymphatic development and function in a wide range of tissues. There are conflicting reports on the distribution of endometrial lymphatics, with some studies reporting lymphatics in the functional zone of human endometrium, others only in the endometrial basalis, and some reporting none at all. Using immunohistochemical methods we have shown that lymphatic vessels of the functionalis were small and sparsely distributed whereas the basalis lymphatics are larger, more frequent and often closely associated with spiral arterioles. Based on comparisons of serial sections, the majority of lymphatic vessels are positive for CD31 but not FVIII or CD34. By comparing CD31 with D2–40 (labels lymphatic endothelial cells) vessel immunostaining, it was estimated that 13% of the vessel profiles in the functionalis, 43% in the basalis and 28% in the myometrium were lymphatics. The lymphangiogenic growth factor VEGF-C is immunolocalized most prominently in the glandular cells, vascular endothelium and some stromal cells in normal cycling endometrium. There is no difference in staining intensity observed between the basalis and functionalis. VEGF-D is immunolocalized throughout the endometrial and myometrial tissues, with no difference in intensity between endometrial glands and stroma or between the basalis and functionalis across the normal cycle. In conclusion, despite an apparently similar distribution of VEGF-C, VEGF-D and VEGF-R3 in endometrial functionalis and basalis, the lymphatic vascular density is 4–5 times higher in the basalis compared to the functionalis. There is also a close association between some lymphatics in the basalis and the spiral arterioles, thus identifying a potential mechanism for a vascular control feedback loop.

Keywords: Endometrium, Lymphangiogenesis, Vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF-R3

 

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1. Introduction 

The lymphatic system has always been a relatively invisible partner in microvascular research, with the vast majority of studies focusing on the blood vascular system. However, major advances in understanding of the molecular mechanisms behind lymphatic growth and development, along with the identification of a number of specific markers for lymphatic endothelial cells (LEC), has led to a recent surge of interest in the lymphatic system. This article will briefly summarise some of the more important advances in understanding of lymph vessel growth, or lymphangiogenesis, and then review current knowledge of the lymphatics and lymphangiogenesis in the endometrium.

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2. Recent advances in the understanding of lymphangiogenesis 

The lymphatics commence in the tissues as blind-ending capillaries which connect to and drain via collecting vessels, lymph nodes, lymphatic trunks and ultimately the thoracic duct into the subclavian veins. Lymphatics collect and drain protein-rich fluid that exudes from the high pressure blood vascular system, returning it to the circulation at a site where the blood pressure is close to its lowest. Loss or impairment of lymphatic function, as occurs with surgical removal of lymph nodes, can cause lymphoedema, where excessive tissue fluid accumulates and cannot drain. In addition to tissue fluid balance, the lymphatics play a central role in immune surveillance of the body. Antigen-presenting cells and lymphocytes travel through the lymphatic vessels from peripheral tissues to the lymphoid organs, where immune defence against pathogens is mounted.

The endothelium of the terminal lymphatics is discontinuous, as is the underlying basement membrane. Anchoring filaments link LEC's to the interstitial extracellular matrix (ECM) so that fluid accumulation in the tissues opens inter-LEC gaps in the terminal lymphatics and enhances the uptake of interstitial fluid. The recent identification of specific LEC markers such as vascular endothelial growth factor receptor-3 (VEGF-R3) a tyrosine kinase receptor that is activated by vascular endothelial growth factor-C (VEGF-C) and VEGF-D [1], lymphatic endothelial hyaluronan receptor-1 (LYVE-1), a transmembrane receptor that binds to glycosaminoglycan hyaluronan [2], podoplanin, a transmembrane glycoprotein that controls podocyte shape and platelet aggregation [3] and prospero-related homeobox-1 (PROX1), a transcription factor [4], has provided the tools to accurately characterise lymphatic distribution in a wide range of tissues. The functional roles of the above LEC markers, as well as a number of other molecules that influence lymphatic structure and function have recently been reviewed [5].

Studies using transgenic mice have demonstrated that lymphangiogenesis occurs under the influence of VEGF-C [6] and VEGF-D [7] acting through VEGF-R3 [8]. VEGF-C and VEGF-D are produced as pre-pro-peptides that are proteolytically cleaved, altering their binding affinity for receptors VEGF-R2 and VEGF-R3 [9], [10]. VEGF-C promotes the initial sprouting of the first PROX1-positive LECs from the jugular vein during development, and induces LEC proliferation and survival [11]. VEGF-C knockout mice fail to form primary lymph sacs, lack all lymphatic vessels, develop severe oedema and die before birth. Even the loss of one VEGF-C allele in heterozygous mice leads to lymphatic-vessel hypoplasia and lymphoedema in the skin [11]. VEGF-D also has lymphangiogenic activity but is not mandatory for lymphatic development. VEGF-C and VEGF-D signal primarily through VEGFR3, although proteolytically processed forms also interact with VEGFR2 [12], [13]. These binding properties, along with the expression of VEGFR3 in blood vessel endothelial cells (BEC) helps to explain the severe vasculogenic and angiogenic defects seen during early embryogenesis in VEGF-R3 knockout mice [14], [15]. Around the time of birth VEGF-R3 expression becomes increasingly confined to the lymphatic vasculature so that disruption of VEGF-C signaling selectively compromises lymphangiogenesis [16], [17]. However, some inhibition of angiogenesis in tumors and wounds has also been observed, and correlates with the re-expression of VEGF-R3 in the blood vessels during these events [18]. Neuropillin-2 (NRP2), which is expressed by LEC, can interact with VEGF-R3 and bind to VEGF-C and VEGF-D, and is essential for lymphangiogenesis [19], [20]. NRP2-knockout mice show reduced LEC proliferation and fail to develop small-diameter lymphatic vessels and capillaries [19]. VEGF-C and VEGF-D also act as ligands for the integrin α9β1, which interacts either independently and/or in conjunction with VEGF-R3 to effect lymphatic endothelial cell adhesion and migration [21]. VEGF-A also stimulates lymphatic growth in experimental systems [22] but this activity might be indirect (for example, through the recruitment of inflammatory cells and increased VEGF-C expression [23]).

Mouse gene knockout and transgenic studies have helped to identify a number of other genes which play fundamental roles in the growth, maturation and function of the lymphatic system. Angiopoietin-2 (ANG2)-deficient mice have defective patterning of the lymphatic network as well as smooth muscle cell (SMC) recruitment to the collecting lymphatics. ANG1 can promote lymphangiogenesis, trigger LEC proliferation and rescue the lymphatic defects of ANG2-knockout mice [24], [25]. Ephrin-B2 is involved in the angiogenic growth of both blood vessels and lymphatic vessels, as shown by LEC sprouting, lymphatic patterning and valve-formation defects in knockout mice [26]. A further feature of the ephrin-B2 mutant is the appearance of ectopic SMC coverage on cutaneous lymphatic capillaries. In these mice, pericytes and vascular SMCs fail to associate stably with blood vessels and some migrate to the lymphatics [27]. The lymphatics in platelet derived growth factor receptor-B (PDGFRB) knockout mice also acquire ectopic vascular SMC, which suggests that intact pericyte and vascular SMC chemotaxis helps to ensure that only the correct vessels acquire mural cells [27]. Similarly, FOXC2-deficient mice have dysfunctional lymphatics that express several BEC markers including PDGFB, are covered by SMC, and lack valves. Normal early lymphatic development in these mice demonstrates that FOXC2 is mainly required for the later maturation steps of lymph vessel formation [28].

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3. Endometrial lymphatics 

While new blood vessel growth, or angiogenesis, has been studied extensively in human endometrium during the menstrual cycle, there is only limited and very recent information on the growth of endometrial lymphatics, or lymphangiogenesis [29], [30], [31]. Initial descriptions of human uterine lymphatics are based on routine histological techniques and dye tracking. There is general agreement that the myometrium contains a network of lymphatic vessels of various sizes [32], [33], however, there are conflicting reports on the distribution of endometrial lymphatics. Some studies report lymphatics in the functional zone of human endometrium [34], while others have only identified lymphatics in the endometrial basalis [33].

We have recently used the specific LEC marker podoplanin to investigate endometrial lymphatic distribution during the menstrual cycle [29]. This work used archival paraffin-embedded full thickness hysterectomy samples (n=23 proliferative phase and n=23 secretory phase) removed from women (42±1.3years of age) with menorrhagia or prolapse. The LEC marker podoplanin co-localizes with a protein formerly known as D2–40 [35], to which a commercially available mouse mAb (Signet Laboratories; Dedham, USA) is available. D2–40 was selected for use in this work following pilot immunohistochemical studies with commercially available antibodies against D2–40, LYVE-1 and VEGF-R3 under a variety of conditions. We found that D2–40 was consistently more sensitive and robust in identifying lymphatic endothelium than the other two markers, and found no evidence for cross-reactivity with blood vessel endothelium. Serial tissue sections were stained for four endothelial cell markers: CD31, CD34, factor VIII (FVIII) and D2–40, as well as the lymphangiogenic growth factors VEGF-C and VEGF-D.

Lymphatic vessels of the functionalis were small and sparsely distributed whereas the basalis lymphatics were larger and often closely associated with spiral arterioles (Fig. 1). Myometrial lymphatic vessels were located within the connective tissue matrix between smooth muscle bundles. There was no significant difference between proliferative and secretory lymphatic vessel density (LVD) within the functionalis (proliferative 16.7±2.6vessels/mm2; secretory 16.2±2.6vessels/mm2), basalis (proliferative 73.1±3.7vessels/mm2; secretory 79.1±7.5vessels/mm2) and myometrium (proliferative 63.4±2.7vessels/mm2; secretory 60.3±2.6vessels/mm2). The LVD of the functionalis was significantly reduced when compared with the basalis and the myometrium across the cycle (P=0.001). The basalis contained significantly more lymphatic vessels than the myometrium during the secretory phase (P=0.02). Based on comparisons of serial sections, the majority of D2–40 lymphatic vessels were positive for CD31 (Fig. 1) but not FVIII or CD34. By comparing CD31 with D2–40 vessel immunostaining, it was estimated that 13% of the vessel profiles in the functionalis, 43% in the basalis and 28% in the myometrium were lymphatics.

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  • Fig. 1 

    Immunohistochemistry showing reduced endometrial lymphatics in functionalis (upper left) compared to basalis (upper right). Lymphatic vessels identified by D2–40 (blue). Mid left panel shows D2–40 lymphatics with smooth muscle actin (brown). Mid right panel shows serial section stained with anti-CD31 which identifies blood and lymphatic vessels. Lower panel shows lymphatic vessels intimately associated with a spiral arteriole in the basalis. Gl, gland; Lym, lymphatic; BV, blood vessel; SA, spiral arteriole.

In contrast to our work [29], 2 other recent papers have reported an absence of endometrial lymphatics in the human [30], [31]. Using immunostaining against LYVE-1, the first of these studies reported that human non-pregnant endometrium lacked lymphatic vessels, although pregnancy rapidly induced lymphangiogenesis in the decidual portions of the uterus [30]. In the second study based on 15 surgical samples of normal endometrium taken at various phases of the menstrual cycle, there were no LYVE-1 positive vessels in normal endometrial tissues, whereas a dense CD31 positive vascular network was noted [31].

The limited numbers of lymphatics found in the functionalis, coupled with the presence of a rich lymphatic network in the basalis, could help to explain why some studies have reported a significant presence of endometrial lymphatics [29], [34], while others have found none [30], [31], [32], [33]. Although the lymphatic system plays a major role in both tissue fluid balance and immune surveillance, the functional significance of the reduced lymphatic presence in the functionalis remains speculative at this stage. It is possible that the establishment of pregnancy and survival of the fetal allograft is facilitated by the reduced lymphatic drainage of the endometrium. The sparse lymphatic drainage of the functionalis does provide a functional explanation for the oedema that has long been recognized as a histological feature of the superficial endometrium at specific stages of the menstrual cycle [36].

An intriguing observation from this study was the close association of some lymphatics with the spiral arterioles (Fig. 1). Spiral arterioles are a key feature in the endometrium of menstruating primates, and play a central role both in menstruation and placentation. The observation that lymph fluid returning from the endometrial functionalis and basalis can come into intimate contact with the smooth muscle cells in the wall of the spiral arterioles supplying blood to the endometrium opens the possibility of a novel mechanism of regulation for these specialized vessels. This mechanism would allow for any factors secreted by the endometrium, or the implanting embryo, to have a direct route via the lymphatics to the spiral arteriole wall, where they have the potential to influence blood flow through vasodilation or constriction. Discovering whether such mechanisms play a role in, for example, vasoconstriction associated with cessation of menstruation, will require further investigation.

There are other immunological implications arising from the reduced lymphatic circulation in the functionalis. Reduced anti-sperm antibody production, as well as autoantigen production to menstrual debris, could be looked upon as potentially positive considerations. However, the endometrium is also regularly exposed to foreign pathogens and infection is not uncommon. Perhaps monthly shedding of the non-pregnant endometrial functionalis is one mechanism to help combat exposure to foreign antigens, and thus compensate for any reduced immune surveillance that occurs due to the very limited lymphatic circulation in this highly specialised tissue.

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4. Regulation of endometrial lymphangiogenesis 

VEGF-C has been localized by immunohistochemistry in endometrial stroma, epithelium, blood vessels and on large thin-walled vessels assumed to be lymphatics [37], [38], while VEGF-D immunolocalisation has been reported as low to negative in normal endometrial tissue [39]. To date there has only been one study investigating the presence of the different proteolytically processed forms of VEGF-C and VEGF-D in endometrium [29].

In studies undertaken in our laboratory [29], the angiogenic and lymphangiogenic growth factor VEGF-C was immunolocalized most prominently in the glandular cells, vascular endothelium and some stromal cells in normal cycling endometrium (Fig. 2). The staining intensity was moderate when compared with background or negative controls and there was no difference in staining intensity observed between the basalis and functionalis. VEGF-D was immunolocalized with a moderate level of staining intensity throughout the endometrial and myometrial tissues, with no difference in intensity observed between endometrial glands and stroma or between the basalis and functionalis across the normal cycle (Fig. 2).

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  • Fig. 2 

    VEGF-C, VEGF-D and VEGF-R3 expression in normal endometrium across the menstrual cycle. VEGF-C was primarily localised within the endometrial glands (a) while VEGF-D distribution was heterogeneous throughout the endometrial and myometrial tissues (b). By Western analysis expression of the 58kD peptide of VEGF-C was significantly increased during the proliferative phase compared to the secretory phase. The remaining VEGF-C peptides (41kD, 31kD and 21kD) were not significantly altered across the cycle (c). VEGF-D peptides (56kD, 41kD, 31kD and 21kD) were unchanged across the normal cycle (d). VEGF-R3 peptides (148kD and 65kD) were not significantly changed across the normal cycle (e). Magnification a–b, bar=100μm. g, glands; m, myometrium (from Ref. [28], Donoghue JF, Lederman FL, Susil BJ and Rogers PAW, Lymphangiogensis of Normal Endometrium and Endometrial Adenocarcinoma. Human Reproduction, 2007;22:1705–13. © European Society of Human Reproduction and Embryology. Reproduced by permission of Oxford University Press/Human Reproduction).

Analysis of endometrial protein extracts by SDS-PAGE demonstrated VEGF-C peptides of 58, 41, 31 and 21kD representing full length, partially processed and fully processed peptides (Fig. 2). The endometrial expression of VEGF-C 58kD peptide was significantly reduced during the secretory phase (0.9±0.2ODmm−2) when compared with the proliferative phase (2.5±0.6ODmm−2) (P=0.03), whereas the remaining peptides were not significantly different across the cycle. The endometrial protein extracts contain VEGF-D proteins of 56, 41, 31 and 21kD, with no significant difference in the expression levels of each protein across the cycle (Fig. 2). VEGF-R3, the receptor for VEGF-C and VEGF-D, was demonstrated in endometrial protein extracts as ∼148 and 65kD peptides (Fig. 2). There was a tendency for the 65kD peptide to be more abundant than the 148kD peptide across the cycle, while the expression of both peptides tended to decrease from the proliferative to secretory phase of the cycle, however neither of these results were significant.

There is currently no obvious mechanistic reason for the finding that the basalis has approximately four to five times as many lymphatic vessels as the functionalis, and as yet, no information is available about the relative proliferation rates of lymphatic endothelial cells in the functionalis versus basalis layers. Immunohistochemical results showed no difference in relative immunostaining for the lymphangiogenic factors VEGF-C or VEGF-D between functionalis and basalis, suggesting that differential expression of these growth factors alone does not provide the answer. However, immunohistochemistry does not differentiate between the different peptide forms of VEGF-C and VEGF-D that result from proteolytic processing. Western analysis demonstrated that the more biologically active, proteolytically processed 21kD forms of each protein were present in the endometrium, although samples for the Western work came from whole endometrium, rather than functionalis or basalis separately. Thus, it is possible that the more biologically active 21kD forms of these proteins are predominantly found in the basalis, and that proteolytic processing is restricted in the functionalis. Alternatively, lymphangiogenic growth factors other than VEGF-C or VEGF-D may be involved, or the endometrial functionalis may be a source of lymphangiogenesis inhibitors.

There is minimal evidence for hormonal or menstrual cycle associated regulation of endometrial lymphatic growth. LVD did not change across the menstrual cycle, and the only growth factor peptide to show any difference in expression was the full length or 58kD form of VEGF-C, which was elevated in the proliferative phase. Our Western data demonstrate that normal endometrium must express the proteolytic enzymes necessary to process VEGF-C and VEGF-D. Investigation of which enzymes these are and how they are regulated might provide further insights into how lymphangiogenesis is regulated in the human uterus.

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5. Conclusions 

In conclusion, despite an apparently similar distribution of VEGF-C, VEGF-D and VEGF-R3 in endometrial functionalis and basalis, the lymphatic vascular density is 4–5 times higher in the basalis compared to the functionalis. There is also a close association between some lymphatics in the basalis and the spiral arterioles, thus identifying a potential vascular control feedback loop.

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6. Conflict of interest 

The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.

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Acknowledgements 

This work was supported by the NH&MRC Project Grant No. 384195 to PAWR and JEG. J Donoghue was supported by an Australian Postgraduate Award. PAWR salary provided by NH&MRC Fellowship No. 334063.

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PII: S0143-4004(07)00235-4

doi:10.1016/j.placenta.2007.09.009

Placenta
Volume 29, Supplement , Pages 48-54, March 2008

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