| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
REVIEW |
Centre for Women's Health Research, Department of Obstetrics and Gynaecology and Monash Institute of Medical Research, Monash University, Melbourne, Victoria 3168, Australia
Correspondence should be addressed to J E Girling at Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia; Email: jane.girling{at}med.monash.edu.au
This paper is one of four papers that form part of a special Focus Issue section on Vascular Function in Female Reproduction. The Guest Editor for this section was H N Jabbour, Edinburgh, UK.
 |
Abstract |
|---|
|
Introduction |
|---|
|
Endometrial angiogenesis |
|---|
Angiogenesis is known to occur at all stages of the menstrual cycle (Girling & Rogers 2005). After menstruation, the vessels of the basalis are repaired following shedding of the functionalis. During the proliferative phase, growth of new vessels must match the rapid regrowth of the functionalis. In the secretory phase, the subepithelial capillary plexus matures and the specialised spiral arterioles grow and coil (Kaiserman-Abramof & Padykula 1989). Detailed stereological data show that elongative angiogenesis occurs as the functionalis regrows during the proliferative phase (Gambino et al. 2002). During the secretory phase, a form of branching angiogenesis is thought to occur. This is believed to be intussusception; however, confirmation of this will require either in vivo digital recording of developing human endometrium or use of a specific marker of intussusception, neither of which are currently possible.
There is also evidence illustrating an important role for endothelial progenitor cells in endometrial angiogenesis, with several studies demonstrating the presence of donor-derived endothelial cells within the uterus after bone marrow transplant from either male mice or transgenic mice with endothelial cell-specific mutations (Asahara et al. 1999, Masuda et al. 2007, Mints et al. 2008). In a human study, endothelial cells with an XY genotype were detected in the endometrium of a women receiving an allogenic transplant with bone marrow derived from a male (Mints et al. 2008). The extent of endothelial progenitor cell incorporation is influenced by circulating hormones. In a study by Masuda et al. (2007), ovariectomised mice received a bone marrow transplant from transgenic mice expressing β-galactosidase under the regulation of the endothelial cell-specific promoter TIE2. In these animals, oestrogen, but not progesterone, treatment caused a significant increase in bone marrow-derived endothelial progenitor cells incorporated into the growing uterine vasculature. Further research is required to elucidate the relative contribution of proliferation versus progenitor cell incorporation in the elongative and branching angiogenesis that occurs during the formation of a mature endometrial vasculature.
|
Endometrial lymphangiogenesis |
|---|
Until recently, the distribution of lymphatics within the endometrium has been controversial. Two studies (one in rat and one in human) used functional assays to describe uterine lymphatic vessels. Results from both studies illustrated rapid lymphatic drainage of India ink from the myometrium, but no or minimal drainage when the ink was delivered to the endometrium (Head & Lande 1983, Ueki 1991). Histological studies examining lymphatic vasculature in the rodent endometrium have also been conducted. Two studies report numerous lymphatic vessels in the myometrium with minimal/absent lymphatics in the endometrium (Head & Seeling 1984, Lauweryns & Cornillie 1984). In contrast, a study using three different morphological/histological techniques found numerous endometrial lymphatics in the rat, particularly in the basal, anti-mesometrial portion of the endometrium during dioestrus (Uchino et al. 1987). One study of human endometrium observed lymphatic vessels in the functionalis region in approximately two-thirds of the samples examined (Blackwell & Fraser 1981).
In recent years, specific lymphatic endothelial cell markers have been identified enabling detailed studies of lymphatic growth and function. These markers include D2–40 (antibody against podoplanin) and lymphatic endothelial hyaluronan receptor 1 (LYVE1), both of which have been used to examine the location and density of lymphatic vessels in human uterus across the menstrual cycle. In a study with D2–40, the basalis exhibited the highest lymphatic vessel density, with similar densities to that observed in the myometrium (Donoghue et al. 2007). In contrast, the functionalis had the lowest number of lymphatic vessels, although the presence of even a small population of vessels in this region confirms the endometrium as a site of regular, physiological lymphangiogenesis. There was no significant change in lymphatic vessel density between proliferative and secretory phase samples. Interestingly, in studies using LYVE1 as a marker, lymphatic vessels were not observed in the endometrium (Koukourakis et al. 2005, Red-Horse et al. 2006). LYVE1 is a specific and widely used marker of lymphatic vessels. The heterogeneity of LYVE1 immunostaining in the uterus highlights our limited understanding of the phenotype, function and activity of the endometrial lymphatic vessels.
|
Endometrial vascular maturation |
|---|
 TopAbstractIntroductionEndometrial angiogenesisEndometrial lymphangiogenesis Endometrial vascular maturation Regulation of endometrial...ConclusionsDeclaration of interestAcknowledgementsReferences |
|---|
In addition to angiogenesis and lymphangiogenesis, mural cell recruitment and vascular maturation are key to the development of a functional endometrial vasculature (see Rogers & Abberton (2003) for review). One of the earliest differentiation markers of mural cells is 
-smooth muscle actin (-SMA, now known as ACTA2). It is present on both VSMC and pericytes throughout the endometrial vascular tree (Abberton et al. 1996, 1999a, Kohnen et al. 2000, Rogers & Abberton 2003). Other differentiation markers include myosin heavy chain, smooth muscle myosin and 
-SMA. These markers have a more restricted distribution within the endometrial vasculature, suggesting spatial differences in endometrial mural cell phenotypes (Abberton et al. 1999a, Kohnen et al. 2000). It is not known whether the phenotypic differences reflect variation in mural cell function, or different levels of mural cell differentiation within the endometrium.
Vascular maturation is known to occur during the secretory phase of the menstrual cycle (Rogers & Abberton 2003). Proliferation of VSMC has been examined using immunohistochemistry with antibodies directed against -SMA and proliferating cell nuclear antigen (PCNA; Abberton et al. 1999b). Total VSMC cell proliferation was low during the early stages of the menstrual cycle (2–2.5% of PCNA-positive VSMC cells), increasing significantly during the mid-late secretory phase (
4%). This increase reflected proliferation of VSMC surrounding the spiral arterioles. No changes in VSMC proliferation were observed between the proliferative or secretory phases for the straight arterioles. The mechanisms responsible for the differential regulation of different arteriole types are not known.
|
Regulation of endometrial vascular remodelling |
|---|
Within the endometrium, growth and remodelling of the vasculature is either a direct or indirect consequence of changes in the circulating concentrations of the ovarian steroids oestrogen and progesterone. Increasing concentrations of oestrogen are associated with the rapid vessel growth occurring during the proliferative stage of the menstrual cycle. During the secretory phase, maturation of the subepithelial capillary plexus and the growth and coiling of spiral arterioles are regulated by progesterone. In contrast, the endometrial repair that occurs peri-menstruation takes place following the withdrawal of ovarian hormones.
Although endometrial vascular remodelling is under the overall control of oestrogen and progesterone, these hormones act indirectly via numerous other regulators. The current review will focus on three members of the VEGF family (VEGFA, VEGFC, VEGFD) and their receptors, and the ANG–TIE signalling system. Although not addressed in this review, the importance of other regulators, including (but not limited to) fibroblast growth factor, thrombospondin, relaxin, adrenomedullin, the prostaglandins, the prokineticins and the matrix metalloproteinases, cannot be overstated (see Nikitenko et al. 2000, Jabbour et al. 2006, Maldonado-Perez et al. 2007, Parry & Vodstrcil 2007, Chennazhi & Nayak 2009) and references therein for additional information). Considerable effort is still required to understand the complex interactions between these regulators in endometrial vascular remodelling.
Vascular endothelial growth factor-A
Members of the VEGF family and their receptors are key mediators of physiological and pathological vascular remodelling throughout the body. The family includes VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor. As outlined in Fig. 1, family members have variable interactions with the VEGF receptors, which include the receptor tyrosine kinases VEGFR1 (FLT1), VEGFR2 (FLK1, KDR) and VEGFR3 (FLT4), as well as co-receptors from the semophorin family neuropilin 1 (NRP1) and NRP2.
|
VEGFA mRNA and protein are expressed by both the epithelium and stroma of the primate and rodent endometrium, with temporal and spatial changes apparent during the menstrual cycle (Charnock-Jones et al. 1993, Shifren et al. 1996, Torry et al. 1996, Sharkey et al. 2000, Graubert et al. 2001, Lee et al. 2008). The expression patterns reported are not consistent and are therefore difficult to interpret. However, several studies do report the highest expression of VEGFA during the menstrual phase of the cycle (Charnock-Jones et al. 1993, Sharkey et al. 2000, Graubert et al. 2001).
Cyclic changes in VEGFA expression are consistent with regulation by ovarian steroids. Oestrogen is known to affect VEGFA mRNA and protein levels in vitro; however, inconsistent results have been reported. In several studies, VEGFA mRNA and protein expression is increased in endometrial cells in response to oestradiol-17β (E2) treatment (Charnock-Jones et al. 1993, Shifren et al. 1996, Huang et al. 1998, Classen-Linke et al. 2000). In contrast, other studies report no effect of E2 or progesterone treatment on endometrial epithelial or stromal cell VEGFA expression (Sharkey et al. 2000, Lockwood et al. 2002).
Oestrogen treatment has also been shown to affect both temporal and spatial VEGFA expression in the endometrium in vivo. The spatial changes in expression are highlighted by work in ovariectomised, oestrogen-treated mice (Ma et al. 2001). Vegfa expression increased in endometrial stromal cells within 2 h. By 24 h post-administration, there was no stromal Vegfa and expression was restricted to the epithelium. In the baboon and rhesus monkey, endometrial stromal and epithelial VEGFA expression was restored by E2 treatment following a reduction after ovariectomy (Nayak & Brenner 2002, Niklaus et al. 2003). In baboon endometrium, VEGFA mRNA levels were increased in both stromal and glandular epithlelium (measured in samples collected by laser capture microscopy) within 2 h of E2 administration and remained elevated during the 6 h experiment (Aberdeen et al. 2008).
Irrespective of how VEGFA expression is regulated by oestrogen, it is apparent that this growth factor is critical to oestrogen-induced endometrial vascular remodelling. In recent studies with marmosets, proliferative phase endothelial cell proliferation was inhibited if the animals were treated with the VEGFA trap Aflibercept (Fraser et al. 2008). As VEGFA is also required for ovarian oestrogen production, it was possible that the endometrial effects were due to the low circulating hormone levels. However, oestrogen replacement in these animals only partially restored endometrial angiogenesis. In addition, endothelial cell proliferation was reduced in ovariectomised marmosets and restored by oestrogen treatment. In mice and baboons also, E2-induced endothelial cell proliferation can be inhibited if VEGFA is blocked (Heryanto et al. 2003, Aberdeen et al. 2008).
Considerably less attention has been paid to the interactions between progesterone and VEGFA, despite the important endometrial vascular remodelling occurring during the progesterone-regulated secretory phase. In ovariectomised mice, progesterone-induced endothelial cell proliferation, but not mural cell proliferation, was significantly reduced when mice were concurrently treated with a VEGF antiserum (Walter et al. 2005, Girling et al. 2007). In comparison to the relatively rapid effects of oestrogen on VEGFA production and endothelial cell proliferation, the effects of progesterone are slower and of a lower magnitude. In the study by Ma et al. (2001), Vegfa increased steadily within the endometrial stroma over a 24 h period in response to a single progesterone injection.
Menstruation is a result of oestrogen and progesterone withdrawal at the end of the menstrual cycle. It is believed to be initiated by tissue breakdown within the functionalis, with associated vascular breakdown and bleeding (see Salamonsen (2003) for review). It has been hypothesised that the bleeding events are focal and halted by vasoconstriction of spiral arterioles in the basalis. Repair of the endometrial vasculature begins while menstruation is still in progress. This means that vascular breakdown and repair are occurring concurrently at different sites within the endometrium.
Menstrual angiogenesis is thought to be a hypoxia-related process. Support for this comes from Markee's experiments in which endometrial explants were transplanted into the anterior chamber of the eye in rhesus macaques (Markee 1940). Vasoconstriction followed by vasodilation of the spiral arterioles was observed following progesterone withdrawal. If such vasoconstriction occurred in the endometrium in situ, it would provide a possible mechanism for vessel repair through hypoxia-induced upregulation of VEGFA. Several studies have observed the highest expression of VEGFA during the menstrual phase of the menstrual cycle (Charnock-Jones et al. 1993, Sharkey et al. 2000, Graubert et al. 2001). In addition, more SLC2A1 (a glucose transporter and marker of anaerobic metabolism that is induced by ischaemia, previously known as GLUT1) was found in endometrial samples from menstruating women in comparison to proliferative or secretory phase samples (Graubert et al. 2001). High levels of VEGFA mRNA were observed in the glands, stroma and necrotic areas of menstrual phase endometrium (Charnock-Jones et al. 1993, Sharkey et al. 2000). In artificially-cycling macaques, VEGFA mRNA was upregulated in the glands and stroma of superficial endometrial tissues 1–2 days following progesterone withdrawal (Nayak & Brenner 2002). VEGFA expression and secretion is also increased in endometrial epithelial and stromal cells exposed to hypoxic conditions in vitro (Popovici et al. 1999, Sharkey et al. 2000, Lockwood et al. 2002).
Mechanistic support for a role of VEGFA in endometrial vascular repair is provided by a recent study using the artificially-cycling macaque model. The macaques were treated with VEGF trap during endometrial regeneration. This inhibited angiogenesis and also slowed re-epithelisation following endometrial breakdown (Fan et al. 2008). There was no effect of the VEGF trap on pre-existing vessels. These results suggest that VEGF is only essential for the formation of new vessels, not the survival of mature endometrial vessels, a finding that has important implications for our understanding of VEGF function in the endometrium.
Similar results were also observed in studies with a decidualised mouse model (Fan et al. 2008). After hormone withdrawal to stimulate endometrial breakdown, the endometrial tissue undergoing repair (stroma adjacent to the lumen) stained strongly with a marker of hypoxia (Hypoxyprobe-1) as well as VEGFA. Use of a VEGFA trap in these mice significantly inhibited vascularisation of the regenerating stroma. The authors hypothesise that ischemic hypoxia in the uppermost regions of the endometrium is the local stimulus for VEGFA expression and the subsequent angiogenesis (Fan et al. 2008).
However, despite the above observations, there is no direct evidence for vasoconstriction or hypoxia during menstruation in human endometrium (Salamonsen 2003). Peri-menstruation, no significant changes in blood flow were observed and no ischaemia/reperfusion episodes have been detected (Fraser & Peek 1992). Only very low levels of hypoxia-inducible factor 1 (HIF1A) and HIF2A, early markers of hypoxia, have been observed in the human endometrium (Gannon et al. 1997). An alternative theory to vasoconstriction and hypoxia suggests that menstruation is an inflammatory-type process (Salamonsen 2003). Future research will need to carefully address the two potential mechanisms, including examining the role of various inflammatory mediators in endometrial vascular remodelling.
In both primates and rodents, the strongest expression of VEGFA is observed in the endometrial epithelium. However, an in vitro study has illustrated that most epithelial VEGFA is secreted into the uterine lumen via the apical cell surface (Hornung et al. 1998). Based on these observations, it was hypothesised that epithelial VEGF is unlikely to have a role in endometrial angiogenesis. However, there is also the potential for paracrine interactions between the epithelium and endometrial stroma. Experiments were conducted in which endometrial epithelial and stromal cells were co-cultured with human myometrial microvascular endothelial cells (Albrecht et al. 2003). In comparison to culture in media only, myometrial microvascular endothelial cell tube formation increased when endothelial cells were cultured in media supplemented with human recombinant VEGFA or co-cultured with endometrial epithelial cells. A further increase occurred when endothelial cells were treated with oestrogen and co-cultured with endometrial epithelial cells. No such increase was observed when the endothelial cells were co-cultured with endometrial stromal cells (Albrecht et al. 2003). These results are consistent with a paracrine role for epithelial VEGFA in endometrial angiogenesis. However, as directional secretion (from the apical surface) does not occur in vitro, additional studies will be required to determine whether epithelial VEGFA is normally secreted into the endometrial stroma in vivo.
It must also be remembered that in addition to stromal and epithelial cells, the endometrium contains a large population of leucocytes that undergo cyclic-dependent changes in number and type during the menstrual cycle. Leucocytes may contribute to endometrial vascular remodelling by expressing and secreting angiogenic factors, or by simulating production of local factors required for vascular remodelling including VEGFA (recently reviewed by Dunk et al. (2008)). Neutrophils have been hypothesised to have a specific role in endometrial angiogenesis. Foci of intense VEGFA immunostaining correlating temporally and spatially with endothelial cell proliferation in the human endometrium were found to be VEGFA expressing neutrophils (Gargett et al. 2001). Studies in mice further support a role for neutrophils in endometrial angiogenesis (Heryanto et al. 2004). Induction of neutropenia significantly reduced oestrogen-induced endometrial endothelial cell proliferation by 30–40%. Macrophages also express VEGFA, although whether these cells have a specific role in endometrial vascular remodelling has not yet been examined.
Various studies have now shown that the different VEGFA isoforms are present in the endometrium (Charnock-Jones et al. 1993, Halder et al. 2000, Sharkey et al. 2000, Ancelin et al. 2002, Niklaus et al. 2002, Sugino et al. 2002). As in other tissues, VEGFA164 is believed to be the dominant isoform in human endometrium. VEGFA121, VEGF145 and VEGFA189 are also present and are thought to be hormonally regulated. To fully understand the role of VEGFA in endometrial vascular remodelling, studies will need to address the location and specific activity of VEGFA isoforms. This is particularly important now with the recent identification of anti-angiogenic VEGFAb isoforms.
In addition to different interactions with the VEGF receptors, VEGFA isoforms have differing interactions with the extracellular matrix (Robinson & Stringer 2001, Ferrara 2004). VEGFA121 is freely soluble, whereas VEGFA145 and VEGFA189 are largely bound to the extracellular matrix; VEGFA165 has intermediate properties. The bound forms provide a reservoir of VEGFA that can be released by a number of proteases (heparin, heparin sulphate, heparinase, plasmin or urokinase-type plasminogen activator) to provide a bioactive VEGFA fragment that can interact with the VEGFA receptors. As yet, nothing is known about the cyclic or hormone-induced changes in stored VEGFA. Protein analyses able to illustrate the distribution of bound versus unbound VEGFA and the changes in this distribution in response to hormone-treatment would be useful.
Vascular endothelial growth factor-C and -D
VEGFC and VEGFD are known for their key role in lymphangiogenesis, although they are also regulators of angiogenesis (Baldwin et al. 2002, Karpanen & Alitalo 2008). Increases in blood and lymph vessel size have previously been observed in muscle treated with adenovirus expressing VEGFC or VEGFD (Rissanen et al. 2003, Kholova et al. 2007) and in regenerating skin treated with transfected tumour cells expressing VEGFC (Goldman et al. 2005). VEGFC and VEGFD bind and activate VEGFR2 and VEGFR3, which in the adult are found predominantly on blood and lymphatic endothelial cells, respectively. These growth factors differ from other members of the mammalian VEGF family because of the presence of pro-peptides at both the N- and C-termini of the conserved VEGF homology domain. Proteolytic cleavage of the pro-peptides by plasmin modulates bioactivity of both molecules, increasing affinity for both VEGFR2 and 3.
Both VEGFC and VEGFD are expressed by the endometrium. To date, studies have reported variable levels of VEGFC immunostaining in the stroma, glands and blood vessels of normal human endometrium (Mints et al. 2002, Moller et al. 2002). Low levels of constitutively expressed VEGFC mRNA were observed in endometrial biopsies collected throughout the menstrual cycle (Graubert et al. 2001). In our own studies, we found the highest level of VEGFC immunostaining in the glandular epithelial cells, the vascular endothelium and in a proportion of stromal cells (Donoghue et al. 2007). Of note, there was no difference in staining intensity between the functionalis and basalis, despite the different density of lymphatic vessels between the two endometrial regions.
VEGFD immunostaining has been reported to be low or negative in all compartments of the endometrium (Yokoyama et al. 2003). We observed moderate VEGFD immunostaining throughout the human endometrium and myometrium, with no difference in intensity between the endometrial epithelium and stroma (Donoghue et al. 2007). As with VEGFC, there was no variation in staining intensity between the basalis and functionalis across the normal cycle.
Although VEGFC and VEGFD are present in the human endometrium, no studies have determined whether they have a functional role in endometrial angiogenesis and/or lymphangiogenesis. As with VEGFA, future studies will need to consider epithelial versus stromal VEGFC and VEGFD. Studies will need to take into account the regulation and function of specific isoforms. SDS-PAGE analysis has identified 58, 41, 31 and 21 kDa VEGFC peptides and 56, 41, 31 and 21 kDa VEGFD peptides in the human endometrium (Donoghue et al. 2007). These represent full length, partially processed and fully processed forms of VEGFC and VEGFD, indicating that these key growth factors are both produced and processed in the endometrium. Which cell types and regions within the endometrium express the different isoforms is not known. This information may help explain the different density of lymphatic vessels between the functionalis and basalis.
VEGF and neuropilin receptors
VEGFA, C and D bind in an overlapping pattern to three receptor tyrosine kinases: VEGFR1, VEGFR2 and VEGFR3 (Ferrara 2004, Hoeben et al. 2004, McColl et al. 2004, Olsson et al. 2006; Fig. 1). There is also binding with the co-receptors NRP1 and NRP2. VEGFR2 mediates VEGFA stimulated blood endothelial cell proliferation, while VEGFR1 may be a negative regulator of VEGFA activity and appears to signal some of the more subtle effects of VEGFA, such as endothelial cell migration and modulation of immune function. Negative regulation of VEGFA is also provided by a soluble form of VEGFR1 (sFLT1), which binds to VEGFA preventing binding with VEGFR2 (Olsson et al. 2006). VEGFR3 is important for lymphatic endothelial cell development and function.
The VEGF receptors are able to form both homodimers and heterodimers, although the specific signalling pathways associated with homo versus heterodimers are not known (Olsson et al. 2006). Dimerisation and activation of the receptors leads to autophosphorylation and induces various downstreaming signalling pathways (VEGFR2: phospholipase C (PLC) /protein kinase C (PKC) pathway, C-RAF–MEK–MAP-kinase cascade, phosphoinositide 3-kinase/AKT pathway; VEGFR3: PLC /PKC pathway; refer Olsson et al. (2006), Shibuya (2008), Lohela et al. (2009) and references therein for detailed information) resulting in specific biological responses such as vascular permeability, cell migration or proliferation. Discussion of these signalling pathways is beyond the scope of the current review, except to highlight our lack of understanding of the downstream signalling pathways initiated in response to VEGF receptor activation within the endometrium.
VEGF receptors are primarily expressed in the vasculature and information from various genetic mouse models are consistent with the most important function of these ligand/receptor interactions occurring in the vascular system (Olsson et al. 2006). However, studies in endometrium demonstrate that VEGF receptors are expressed in other cell types as well. In the human endometrium, most studies examining VEGFR1 and VEGFR2 observed the highest expression in the endometrial vasculature. Additional staining is also variously reported in the epithelium, stroma and leucocytes with changes noted between proliferative and secretory phase samples (Meduri et al. 2000, Sugino et al. 2002, Punyadeera et al. 2006, Mints et al. 2007b, Jee et al. 2009). There are also recent publications investigating the immunohistochemical expression of VEGFR3 in human endometrium (Mints et al. 2002, Moller et al. 2002, Yokoyama et al. 2003). Immunostaining was reported in endometrial blood endothelial cells in two of the studies (Mints et al. 2002, Moller et al. 2002), but the third reported no immunostaining in endometrial tissues (Yokoyama et al. 2003). VEGFR3 immunostaining has also been reported in glands of the human endometrium, with weak to moderate immunostaining noted in avascular stroma (Mints et al. 2007a). The function of non-vascular VEGF receptors in the endometrium is not known.
VEGF receptor expression is also thought to be regulated by oestrogen and progesterone. In ovariectomised oestrogen-treated mice, Vegfr2 mRNA increased in endometrial stromal cells within 6 h, but had declined by 24 h (Ma et al. 2001). In contrast, Vegfr2 increased steadily within the endometrial stroma over a 24 h period in response to a single progesterone injection (Ma et al. 2001). In mice treated with E2 or both E2 and progesterone for 21 days, there was an increase in the number of VEGFR2 immunostained vessels in comparison to control animals (Herve et al. 2006). An oestrogen receptor mediated effect was confirmed using similar experiments in oestrogen receptor knockout mice. The proportion of vessel structures immunostaining with VEGFR2 was significantly reduced in knockout animals compared to similarly treated wild-type animals.
Consistent with a hypothesised role for VEGFA in peri-menstrual vascular repair, hormone-withdrawal is also associated with increasing VEGF receptor expression. In artificially cycling macaques, low levels of VEGFR2 mRNA were observed in the proliferative and secretory phases (Nayak et al. 2000). After withdrawal of progesterone, there was a large increase in VEGFR2, but not VEGFR1, mRNA expression. During the proliferative and secretory phase, VEGFR2 expression was confined to the vascular endothelium. After progesterone withdrawal, expression was strongly upregulated in the endometrial stroma with a marked gradient of VEGFR2 mRNA expression from mid way through the functionalis up to the luminal surface. Similar patterns of expression were also described in human premenstrual samples (Nayak et al. 2000).
Graubert et al. (2001) report increases in VEGFR1, sFLT and VEGFR2 expression at menstruation in human endometrium. This study also assessed the functional status of the VEGF receptors. Using immunoprecipitation and western blot analysis with anti-VEGFR2 and anti-phosphotyrosine antibodies, respectively, VEGFR2 phosyphorylation peaked in the late menstrual phase with lower sustained phosphorylation levels during the proliferative phase. Binding of sFLT to VEGFA was observed in the early, but not late menstrual phase (although high levels of VEGFA mRNA were still present in the endometrium; Graubert et al. 2001). This is one of the few studies to begin addressing the activity of VEGF receptors, in addition to their expression. Further studies considering the functional status and downstream signalling from VEGF receptors are required.
In addition to the VEGF receptors, the co-receptors NRP1 and NRP2 are also expressed by the endometrium. They report high expression in the vascular endothelium, with variable expression in the stroma and glandular epithelium (Pavelock et al. 2001, Germeyer et al. 2005, Punyadeera et al. 2006, Hess et al. 2009). However, no studies have yet examined the functional interactions between the neuropilins and VEGF tyrosine kinase receptors in endometrial vascular remodelling.
The angiopoietin–TIE system
Another system key to endothelial cell function with links to the VEGF family is the ANG–TIE (Tyr kinase with Ig and epidermal growth factor homology domains, also known as TEK) signalling system (recently reviewed by Augustin et al. (2009)). The ANG–TIE system is important in vessel maturation and has a role in the regulation of VSMC recruitment. This system is also involved in maintaining blood vessel quiescence. ANG1 activates the TIE2 receptors, whereas ANG2 is described as a ligand that antagonises the activation of TIE2. The consequences of TIE2 inhibition are contextual. If VEGFA is present, ANG2 will enable endothelial cell migration and proliferation and therefore angiogenesis. If VEGFA is inhibited, ANG2 will lead to endothelial cell death and vessel regression (Gale et al. 2002, Augustin et al. 2009).
The ANG–TIE system is also believed to have a role in lymphangiogenesis. This is based on observations in ANG2 deficient mice, which develop chylous ascites prior to birth (Gale et al. 2002, Augustin et al. 2009). While these animals only have mild blood vascular defects, they do have considerable lymphatic abnormalities throughout the body with defective patterning of both small and large lymphatics, as well as poor interactions with and abnormal recruitment of surrounding mural cells. The ANG ligands and TIE2 receptors are expressed by both blood and lymphatic vessels. Whether contextual differences related to ligand presentation occur in the lymphatic vessels, as they do in blood vessels, has not yet been elucidated.
While studies have examined ANG1, ANG2, and TIE2 expression in the human endometrium, the results obtained have differed considerably. Staining has been reported variously in the epithelium, stroma and uterine natural killer cells (reviewed in Rogers & Abberton (2003)). In one study, ANG1 immunostaining was observed in stroma, luminal and glandular epithelium, and endothelial cells, whereas ANG2 was detected in the stroma and glandular epithelium (Hirchenhain et al. 2003). TIE2 was observed in glandular epithelium, as well as in endometrial endothelium. ANG1 mRNA expression peaked in the mid-secretory phase of the menstrual cycle, while ANG2 peaked in the late secretory phase (Lee et al. 2008). These studies did not examine menstrual phase samples. Research examining the functional role of the ANG–TIE system in menstrual vascular repair would be particularly interesting considering the reported contextual effects of ANG2 depending on the presence/absence of VEGFA and the role of this system in vascular maturation and quiescence.
In a detailed study by Nayak et al. (2005), TIE2 and ANG1 expression were examined in the endometrium of rhesus macaques treated sequentially with E2 and progesterone, followed by hormone withdrawal, to mimic a menstrual cycle. While TIE2 (mRNA and protein) expression was restricted to the endothelium, with no marked changes in expression during the artificial menstrual cycle, ANG1 mRNA expression varied in a cell and cycle-stage-dependent manner (examined using in situ hybridisation). ANG1 mRNA was only expressed in the glands of the basalis during the proliferative phase, but expression was observed in the upper glands and the luminal epithelium during the early-mid secretory phases; expression was largely absent from the glands in the late secretory phase and following hormone withdrawal. Of particular note, ANG1 mRNA expression was observed in the VSMC of the spiral arterioles during the early–late secretory phases; this expression correlated closely with VSMC proliferation. The authors hypothesised that ANG1 may have a central role in the progesterone-induced development of the spiral artioles in the primate endometrium.
|
Conclusions |
|---|
Growth and remodelling of the endometrial vasculature is either a direct or indirect consequence of changes in the circulating concentrations of the ovarian steroids oestrogen and progesterone. Oestrogen and progesterone (or withdrawal of these hormones) act directly or indirectly on the endometrial vasculature via numerous vascular and pleiotrophic regulators. The best known of these regulators belong to the VEGF family, although the mechanisms by which these growth factors and their receptors interact to control remodelling of the blood versus lymphatic vasculature is still not understood. Future studies need to examine how the different isoforms of VEGFA, VEGFC and VEGFD are regulated. This will need to include studies examining the expression and distribution of the inhibitory VEGFAb isoforms. Research is also required to address the interaction of various VEGF family members with the extracellular matrix during the menstrual cycle and the function of non-vascular endometrial VEGF receptors and co-receptors. The specific mechanisms leading to differential receptor phosphorylation and specific downstream signalling pathways leading to endometrial endothelial cell permeability, migration and/or proliferation will also need to be elucidated.
A second key group of vascular regulators in the endometrium with interesting interactions with the VEGF family are the ANG–TIE ligands and receptors. These proteins are involved in mural cell recruitment and in the maintenance of vessel quiescence. They also have hypothesised roles in lymphangiogenesis. While ANG1, ANG2 and TIE2 are all expressed by the endometrium, the interactions of the ANG–TIE system with VEGF family members during endometrial angiogenesis, lymphangiogenesis and vascular maturation has not been explored. Continuing research into the detailed activity, function and interaction of both the VEGF family and ANG–TIE system will ultimately enhance our understanding of normal endometrial vascular remodelling and provide information relevant to various disorders and pathologies of the endometrium that have a vascular component.
|
Declaration of interest |
|---|
|
Funding |
|---|
|
Acknowledgements |
|---|
Received April 19, 2009
First decision June 5, 2009
Revised manuscript received August 11, 2009
Accepted September 14, 2009
|
References |
|---|
Abberton KM, Taylor NH, Healy DL & Rogers PA 1996 Vascular smooth muscle -actin distribution around endometrial arterioles during the menstrual cycle: increased expression during the perimenopause and lack of correlation with menorrhagia. Human Reproduction 11 204–211.
Abberton KM, Healy DL & Rogers PA 1999a Smooth muscle actin and myosin heavy chain expression in the vascular smooth muscle cells surrounding human endometrial arterioles. Human Reproduction 14 3095–3100.
Abberton KM, Taylor NH, Healy DL & Rogers PA 1999b Vascular smooth muscle cell proliferation in arterioles of the human endometrium. Human Reproduction 14 1072–1079.
Aberdeen GW, Wiegand SJ, Bonagura TW Jr, Pepe GJ & Albrecht ED 2008 Vascular endothelial growth factor mediates the estrogen-induced breakdown of tight junctions between and increase in proliferation of microvessel endothelial cells in the baboon endometrium. Endocrinology 149 6076–6083.
Albrecht ED, Babischkin JS, Lidor Y, Anderson LD, Udoff LC & Pepe GJ 2003 Effect of estrogen on angiogenesis in co-cultures of human endometrial cells and microvascular endothelial cells. Human Reproduction 18 2039–2047.
Alitalo K, Tammela T & Petrova TV 2005 Lymphangiogenesis in development and human disease. Nature 438 946–953.[CrossRef][Medline]
Ancelin M, Buteau-Lozano H, Meduri G, Osborne-Pellegrin M, Sordello S, Plouet J & Perrot-Applanat M 2002 A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus. PNAS 99 6023–6028.
Armulik A, Abramsson A & Betsholtz C 2005 Endothelial/pericyte interactions. Circulation Research 97 512–523.
Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M & Isner JM 1999 Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circulation Research 85 221–228.
Augustin HG, Young Koh G, Thurston G & Alitalo K 2009 Control of vascular morphogenesis and homeostasis through the angiopoietin–TIE system. Nature Reviews. Molecular Cell Biology 10 165–177.[CrossRef][Web of Science][Medline]
Baldwin ME, Stacker SA & Achen MG 2002 Molecular control of lymphangiogenesis. BioEssays 24 1030–1040.[CrossRef][Web of Science][Medline]
Blackwell PM & Fraser IS 1981 Superficial lymphatics in the functional zone of normal human endometrium. Microvascular Research 21 142–152.[CrossRef][Web of Science][Medline]
Burri PH & Djonov V 2002 Intussusceptive angiogenesis – the alternative to capillary sprouting. Molecular Aspects of Medicine 23 S1–S27.[Medline]
Charnock-Jones DS, Sharkey AM, Rajput-Williams J, Burch D, Schofield JP, Fountain SA, Boocock CA & Smith SK 1993 Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines. Biology of Reproduction 48 1120–1128.[Abstract]
Chennazhi KP & Nayak NR 2009 Regulation of angiogenesis in the primate endometrium: vascular endothelial growth factor. Seminars in Reproductive Medicine 27 80–89.[CrossRef][Web of Science][Medline]
Classen-Linke I, Alfer J, Krusche CA, Chwalisz K, Rath W & Beier HM 2000 Progestins, progesterone receptor modulators, and progesterone antagonists change VEGF release of endometrial cells in culture. Steroids 65 763–771.[CrossRef][Web of Science][Medline]
Donoghue JF, Lederman FL, Susil BJ & Rogers PA 2007 Lymphangiogenesis of normal endometrium and endometrial adenocarcinoma. Human Reproduction 22 1705–1713.
Dunk C, Smith S, Hazan A, Whittle W & Jones RL 2008 Promotion of angiogenesis by human endometrial lymphocytes. Immunological Investigations 37 583–610.[CrossRef][Web of Science][Medline]
Fan X, Krieg S, Kuo CJ, Wiegand SJ, Rabinovitch M, Druzin ML, Brenner RM, Giudice LC & Nayak NR 2008 VEGF blockade inhibits angiogenesis and reepithelialization of endometrium. FASEB Journal 22 3571–3580.
Ferrara N 2004 Vascular endothelial growth factor: basic science and clinical progress. Endocrine Reviews 25 581–611.
Fraser IS & Peek MJ 1992 Effects of exogenous hormones on endometrial capillaries. In Steroid Hormones and Uterine Bleeding , pp 65–79 Eds NJ Alexander & C d'Arcangues. Washington: AAAS Press.
Fraser HM, Wilson H, Silvestri A, Morris KD & Wiegand SJ 2008 The role of vascular endothelial growth factor and estradiol in the regulation of endometrial angiogenesis and cell proliferation in the marmoset. Endocrinology 149 4413–4420.
Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D et al. 2002 Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Developmental Cell 3 411–423.[CrossRef][Web of Science][Medline]
Gambino LS, Wreford NG, Bertram JF, Dockery P, Lederman F & Rogers PA 2002 Angiogenesis occurs by vessel elongation in proliferative phase human endometrium. Human Reproduction 17 1199–1206.
Gannon BJ, Carati CJ & Verco CJ 1997 Endometrial perfusion across the normal human menstrual cycle assessed by laser Doppler fluxmetry. Human Reproduction 12 132–139.
Gargett CE, Lederman F, Heryanto B, Gambino LS & Rogers PA 2001 Focal vascular endothelial growth factor correlates with angiogenesis in human endometrium. Role of intravascular neutrophils. Human Reproduction 16 1065–1075.
Germeyer A, Hamilton AE, Laughlin LS, Lasley BL, Brenner RM, Giudice LC & Nayak NR 2005 Cellular expression and hormonal regulation of neuropilin-1 and -2 messenger ribonucleic acid in the human and rhesus macaque endometrium. Journal of Clinical Endocrinology and Metabolism 90 1783–1790.
Girling JE & Rogers PA 2005 Recent advances in endometrial angiogenesis research. Angiogenesis 8 89–99.[CrossRef][Medline]
Girling JE, Lederman FL, Walter LM & Rogers PA 2007 Progesterone, but not estrogen, stimulates vessel maturation in the mouse endometrium. Endocrinology 148 5433–5441.
Goldman J, Le TX, Skobe M & Swartz MA 2005 Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin. Circulation Research 96 1193–1199.
Graubert MD, Ortega MA, Kessel B, Mortola JF & Iruela-Arispe ML 2001 Vascular repair after menstruation involves regulation of vascular endothelial growth factor-receptor phosphorylation by sFLT-1. American Journal of Pathology 158 1399–1410.
Halder JB, Zhao X, Soker S, Paria BC, Klagsbrun M, Das SK & Dey SK 2000 Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation. Genesis 26 213–224.[CrossRef][Web of Science][Medline]
Harper SJ & Bates DO 2008 VEGF-A splicing: the key to anti-angiogenic therapeutics? Nature Reviews. Cancer 8 880–887.[CrossRef][Web of Science][Medline]
Head JR & Lande IJ 1983 Uterine lymphatics: passage of ink and lymphoid cells from the rat's uterine wall and lumen. Biology of Reproduction 28 941–955.[Abstract]
Head JR & Seeling LL Jr 1984 Lymphatic vessels in the uterine endometrium of virgin rats. Journal of Reproductive Immunology 6 157–166.[CrossRef][Web of Science][Medline]
Herve MA, Meduri G, Petit FG, Domet TS, Lazennec G, Mourah S & Perrot-Applanat M 2006 Regulation of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR by estradiol through VEGF in uterus. Journal of Endocrinology 188 91–99.
Heryanto B, Lipson KE & Rogers PA 2003 Effect of angiogenesis inhibitors on oestrogen-mediated endometrial endothelial cell proliferation in the ovariectomized mouse. Reproduction 125 337–346.[Abstract]
Heryanto B, Girling JE & Rogers PA 2004 Intravascular neutrophils partially mediate the endometrial endothelial cell proliferative response to oestrogen in ovariectomised mice. Reproduction 127 613–620.
Hess AP, Schanz A, Baston-Buest DM, Hirchenhain J, Stoff-Khalili MA, Bielfeld P & Kruessel JS 2009 Expression of the vascular endothelial growth factor receptor neuropilin-1 in the human endometrium. Journal of Reproductive Immunology 79 129–136.[CrossRef][Web of Science][Medline]
Hirchenhain J, Huse I, Hess A, Bielfeld P, De Bruyne F & Krussel JS 2003 Differential expression of angiopoietins 1 and 2 and their receptor Tie-2 in human endometrium. Molecular Human Reproduction 9 663–669.
Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT & De Bruijn EA 2004 Vascular endothelial growth factor and angiogenesis. Pharmacological Reviews 56 549–580.
Hornung D, Lebovic DI, Shifren JL, Vigne JL & Taylor RN 1998 Vectorial secretion of vascular endothelial growth factor by polarized human endometrial epithelial cells. Fertility and Sterility 69 909–915.[CrossRef][Web of Science][Medline]
Huang JC, Liu DY & Dawood MY 1998 The expression of vascular endothelial growth factor isoforms in cultured human endometrial stromal cells and its regulation by 17β-oestradiol. Molecular Human Reproduction 4 603–607.
Jabbour HN, Sales KJ, Smith OP, Battersby S & Boddy SC 2006 Prostaglandin receptors are mediators of vascular function in endometrial pathologies. Molecular and Cellular Endocrinology 252 191–200.[CrossRef][Web of Science][Medline]
Jain RK 2003 Molecular regulation of vessel maturation. Nature Medicine 9 685–693.[CrossRef][Web of Science][Medline]
Jee BC, Suh CS, Kim KC, Lee WD, Kim H & Kim SH, Seoul National University College of Medicine Assisted Reproductive Technology Study G 2009 Expression of vascular endothelial growth factor-A and its receptor-1 in a luteal endometrium in patients with repeated in vitro fertilization failure. Fertility and Sterility 91 528–534.[CrossRef][Web of Science][Medline]
Kaiserman-Abramof IR & Padykula HA 1989 Angiogenesis in the postovulatory primate endometrium: the coiled arteriolar system. Anatomical Record 224 479–489.[CrossRef][Medline]
Karpanen T & Alitalo K 2008 Molecular biology and pathology of lymphangiogenesis. Annual Review of Pathology 3 367–397.[CrossRef][Medline]
Kerjaschki D, Huttary N, Raab I, Regele H, Bojarski-Nagy K, Bartel G, Krober SM, Greinix H, Rosenmaier A, Karlhofer F et al. 2006 Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nature Medicine 12 230–234.[CrossRef][Web of Science][Medline]
Khakoo AY & Finkel T 2005 Endothelial progenitor cells. Annual Review of Medicine 56 79–101.[CrossRef][Web of Science][Medline]
Kholova I, Koota S, Kaskenpaa N, Leppanen P, Narvainen J, Kavec M, Rissanen TT, Hazes T, Korpisalo P, Grohn O et al. 2007 Adenovirus-mediated gene transfer of human vascular endothelial growth factor-d induces transient angiogenic effects in mouse hind limb muscle. Human Gene Therapy 18 232–244.[CrossRef][Web of Science][Medline]
Kohnen G, Campbell S, Jeffers MD & Cameron IT 2000 Spatially regulated differentiation of endometrial vascular smooth muscle cells. Human Reproduction 15 284–292.
Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Gatter KC, Harris AL & Jackson DG 2005 LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer. Journal of Clinical Pathology 58 202–206.
Ladomery MR, Harper SJ & Bates DO 2007 Alternative splicing in angiogenesis: the vascular endothelial growth factor paradigm. Cancer Letters 249 133–142.[CrossRef][Web of Science][Medline]
Lauweryns JM & Cornillie FJ 1984 Topography and ultrastructure of the uterine lymphatics in the rat. European Journal of Obstetrics, Gynecology, and Reproductive Biology 18 309–327.[CrossRef][Web of Science][Medline]
Lee YL, Liu Y, Ng PY, Lee KF, Au CL, Ng EH, Ho PC & Yeung WS 2008 Aberrant expression of angiopoietins-1 and -2 and vascular endothelial growth factor-A in peri-implantation endometrium after gonadotrophin stimulation. Human Reproduction 23 894–903.
Lockwood CJ, Krikun G, Koo AB, Kadner S & Schatz F 2002 Differential effects of thrombin and hypoxia on endometrial stromal and glandular epithelial cell vascular endothelial growth factor expression. Journal of Clinical Endocrinology and Metabolism 87 4280–4286.
Lohela M, Bry M, Tammela T & Alitalo K 2009 VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Current Opinion in Cell Biology 21 154–165.[CrossRef][Web of Science][Medline]
Ma W, Tan J, Matsumoto H, Robert B, Abrahamson DR, Das SK & Dey SK 2001 Adult tissue angiogenesis: evidence for negative regulation by estrogen in the uterus. Molecular Endocrinology 15 1983–1992.
Maldonado-Perez D, Evans J, Denison F, Millar RP & Jabbour HN 2007 Potential roles of the prokineticins in reproduction. Trends in Endocrinology and Metabolism 18 66–72.[CrossRef][Web of Science][Medline]
Markee JE 1940 Menstruation in intraocular endometrial transplants in the rhesus monkey. Contributions to Embryology 177 220–230.
Masuda H, Kalka C, Takahashi T, Yoshida M, Wada M, Kobori M, Itoh R, Iwaguro H, Eguchi M, Iwami Y et al. 2007 Estrogen-mediated endothelial progenitor cell biology and kinetics for physiological postnatal vasculogenesis. Circulation Research 101 598–606.
McColl BK, Stacker SA & Achen MG 2004 Molecular regulation of the VEGF family – inducers of angiogenesis and lymphangiogenesis. Acta Pathologica, Microbiologica, et Immunologica Scandinavica 112 463–480.
Meduri G, Bausero P & Perrot-Applanat M 2000 Expression of vascular endothelial growth factor receptors in the human endometrium: modulation during the menstrual cycle. Biology of Reproduction 62 439–447.
Mints M, Blomgren B, Falconer C & Palmblad J 2002 Expression of the vascular endothelial growth factor (VEGF) family in human endometrial blood vessels. Scandinavian Journal of Clinical and Laboratory Investigation 62 167–175.[CrossRef][Web of Science][Medline]
Mints M, Blomgren B & Palmblad J 2007a Expression of vascular endothelial growth factor receptor-3 in the endometrium in menorrhagia. International Journal of Molecular Medicine 19 909–913.[Web of Science][Medline]
Mints M, Hultenby K, Zetterberg E, Blomgren B, Falconer C, Rogers R & Palmblad J 2007b 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. Fertility and Sterility 88 691–697.[CrossRef][Web of Science][Medline]
Mints M, Jansson M, Sadeghi B, Westgren M, Uzunel M, Hassan M & Palmblad J 2008 Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient. Human Reproduction 23 139–143.
Moller B, Lindblom B & Olovsson M 2002 Expression of the vascular endothelial growth factors B and C and their receptors in human endometrium during the menstrual cycle. Acta Obstetrica et Gynecologica Scandinavica 81 817–824.[CrossRef]
Nayak NR & Brenner RM 2002 Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium. Journal of Clinical Endocrinology and Metabolism 87 1845–1855.
Nayak NR, Critchley HO, Slayden OD, Menrad A, Chwalisz K, Baird DT & Brenner RM 2000 Progesterone withdrawal up-regulates vascular endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque endometrium: potential relevance to menstruation. Journal of Clinical Endocrinology and Metabolism 85 3442–3452.
Nayak NR, Kuo CJ, Desai TA, Wiegand SJ, Lasley BL, Giudice LC & Brenner RM 2005 Expression, localization and hormonal control of angiopoietin-1 in the rhesus macaque endometrium: potential role in spiral artery growth. Molecular Human Reproduction 11 791–799.
Nikitenko LL, MacKenzie IZ, Rees MCP & Bicknell R 2000 Adrenomedullin is an autocrine regulator of endothelial growth in human endometrium. Molecular Human Reproduction 6 811–819.
Niklaus AL, Babischkin JS, Aberdeen GW, Pepe GJ & Albrecht ED 2002 Expression of vascular endothelial growth/permeability factor by endometrial glandular epithelial and stromal cells in baboons during the menstrual cycle and after ovariectomy. Endocrinology 143 4007–4017.
Niklaus AL, Aberdeen GW, Babischkin JS, Pepe GJ & Albrecht ED 2003 Effect of estrogen on vascular endothelial growth/permeability factor expression by glandular epithelial and stromal cells in the baboon endometrium. Biology of Reproduction 68 1997–2004.
Olsson AK, Dimberg A, Kreuger J & Claesson-Welsh L 2006 VEGF receptor signalling – in control of vascular function. Nature Reviews. Molecular Cell Biology 7 359–371.[CrossRef][Web of Science][Medline]
Parry LJ & Vodstrcil LA 2007 Relaxin physiology in the female reproductive tract during pregnancy. Advances in Experimental Medicine and Biology 612 34–48.[CrossRef][Web of Science][Medline]
Pavelock K, Braas K, Ouafik L, Osol G & May V 2001 Differential expression and regulation of the vascular endothelial growth factor receptors neuropilin-1 and neuropilin-2 in rat uterus. Endocrinology 142 613–622.
Peirce SM & Skalak TC 2003 Microvascular remodeling: a complex continuum spanning angiogenesis to arteriogenesis. Microcirculation 10 99–111.[CrossRef][Web of Science][Medline]
Popovici RM, Irwin JC, Giaccia AJ & Giudice LC 1999 Hypoxia and cAMP stimulate vascular endothelial growth factor (VEGF) in human endometrial stromal cells: potential relevance to menstruation and endometrial regeneration. Journal of Clinical Endocrinology and Metabolism 84 2245–2248.
Punyadeera C, Thijssen VL, Tchaikovski S, Kamps R, Delvoux B, Dunselman GA, de Goeij AF, Griffioen AW & Groothuis PG 2006 Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium. Molecular Human Reproduction 12 367–375.
Red-Horse K, Rivera J, Schanz A, Zhou Y, Winn V, Kapidzic M, Maltepe E, Okazaki K, Kochman R, Vo KC et al. 2006 Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation. Journal of Clinical Investigation 116 2643–2652.[CrossRef][Web of Science][Medline]
Risau W 1997 Mechanisms of angiogenesis. Nature 386 671–674.[CrossRef][Medline]
Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, Kholova I, Kauppinen RA, Achen MG, Stacker SA et al. 2003 VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circulation Research 92 1098–1106.
Robinson CJ & Stringer SE 2001 The splice variants of vascular endothelial growth factor (VEGF) and their receptors. Journal of Cell Science 114 853–865.[Abstract]
Rogers PA & Abberton KM 2003 Endometrial arteriogenesis: vascular smooth muscle cell proliferation and differentiation during the menstrual cycle and changes associated with endometrial bleeding disorders. Microscopy Research and Technique 60 412–419.[CrossRef][Web of Science][Medline]
Salamonsen LA 2003 Tissue injury and repair in the female human reproductive tract. Reproduction 125 301–311.[Abstract]
Scavelli C, Weber E, Agliano M, Cirulli T, Nico B, Vacca A & Ribatti D 2004 Lymphatics at the crossroads of angiogenesis and lymphangiogenesis. Journal of Anatomy 204 433–449.[CrossRef][Web of Science][Medline]
Sharkey AM, Day K, McPherson A, Malik S, Licence D, Smith SK & Charnock-Jones DS 2000 Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. Journal of Clinical Endocrinology and Metabolism 85 402–409.
Shibuya M 2008 Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis. BMB Reports 41 278–286.[Web of Science][Medline]
Shifren JL, Tseng JF, Zaloudek CJ, Ryan IP, Meng YG, Ferrara N, Jaffe RB & Taylor RN 1996 Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. Journal of Clinical Endocrinology and Metabolism 81 3112–3118.
Sugino N, Kashida S, Karube-Harada A, Takiguchi S & Kato H 2002 Expression of vascular endothelial growth factor (VEGF) and its receptors in human endometrium throughout the menstrual cycle and in early pregnancy. Reproduction 123 379–387.[Abstract]
Torry DS, Holt VJ, Keenan JA, Harris G, Caudle MR & Torry RJ 1996 Vascular endothelial growth factor expression in cycling human endometrium. Fertility and Sterility 66 72–80.[Web of Science][Medline]
Uchino S, Ichikawa S, Okubo M, Nakamura Y & Iimura A 1987 Methods of detection of lymphatics and their changes with oestrous cycle. International Angiology 6 271–278.[Web of Science][Medline]
Ueki M 1991 Histologic study of endometriosis and examination of lymphatic drainage in and from the uterus. American Journal of Obstetrics and Gynecology 165 201–209.[Web of Science][Medline]
Walter LM, Rogers PA & Girling JE 2005 The role of progesterone in endometrial angiogenesis in pregnant and ovariectomised mice. Reproduction 129 765–777.
Yamazaki Y & Morita T 2006 Molecular and functional diversity of vascular endothelial growth factors. Molecular Diversity 10 515–527.[CrossRef][Web of Science][Medline]
Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, Emoto M, Sakamoto A, Sakamoto T, Maruyama H et al. 2003 Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clinical Cancer Research 9 1361–1369.
This article has been cited by other articles:
 |
|
 |
|
  H N Jabbour Vascular function in female reproduction Reproduction, December 1, 2009; 138(6): 867 - 868. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
