Robert S. Robinson1 and Kathryn J. Woad1
(1)
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire, LE12 5RD, UK
Robert S. Robinson (Corresponding author)
Email: bob.robinson@nottingham.ac.uk
Kathryn J. Woad
Email: katie.woad@nottingham.ac.uk
Abstract
The structure and function of the corpus luteum (CL) is dependent on the development of an intricate vasculature via the process of angiogenesis. The establishment of the luteal vascular network begins in the preovulatory follicle and is ultimately stimulated by the luteinizing hormone (LH) surge. Following ovulation, the corpus luteum undergoes extremely rapid growth and intense angiogenesis that is tightly regulated by a balance achieved between pro-angiogenic and anti-angiogenic factors. This review summarizes what is known about the critical control of luteal angiogenesis and the complex interplay between numerous factors, the functions of which are only just beginning to be elucidated.
Keywords
Corpus luteumLutealAngiogenesisVasculatureFGF2VEGFAEndothelialPericyte
1.1 Critical Importance of Luteal Angiogenesis
The principal function of the corpus luteum (CL) is to produce vast quantities of progesterone , which is absolutely essential for the establishment and maintenance of mammalian pregnancy. Groundbreaking work by the research labs of Hamish Fraser and Dick Stouffer in the early 2000s elegantly demonstrated the wholly crucial role of angiogenesis and the extensive vascularization required for the development and function of the CL. Namely, the inhibition of vascular endothelial growth factor-A (VEGFA, pro-angiogenic factor) with targeted antibody or soluble VEGF receptor isoforms completely prevented luteal vascularization and progesterone production [1–3] in primates. Similarly, in cows, the local neutralization of either VEGFA or fibroblast growth factor-2 (FGF2) also suppressed luteal development and progesterone production, albeit to a lesser extent [4]. Additional evidence of the crucial role of luteal angiogenesis for CL functions has been demonstrated using transgenic, knockout or knock-in mice models in which angiogenesis has been directly or indirectly targeted. Table 1.1summarizes such studies where ovulation appeared normal but CL development and function was disrupted. Overall, compromised plasma progesterone levels were associated with disrupted luteal vascularization and reduced fertility, providing further evidence for the close relationship between luteal angiogenesis and function.
Table 1.1
Summary of knockout mouse studies in which ovulation occurred but corpus luteum (CL) function was disrupted
|
Gene |
Plasma P4 levels |
Steroidogenic enzyme and/or StAR expression |
Luteal vascularization |
Fertility |
Reference |
|
Brain and muscle ARNT-like protein 1 (Bmal1) |
↓ |
↓ ↑ |
↑ VEGFA |
Infertile |
[115] |
|
Cyclin-dependent kinase 4 (cdk4) |
↓ |
Unaffected |
n.d. |
Infertile |
[116] |
|
Endothelial nitric oxide synthase (eNOS) |
↑ |
n.d. |
n.d. |
n.d. |
[117] |
|
Fibroblast growth factor-2 (FGF2) |
n.d. |
n.d. |
n.d. |
Normal |
[117] |
|
Frizzled4 (Fzd4) |
↓ |
↓ |
Fragmented and punctate vascular network ↓ VEGFA |
Infertile |
[118] |
|
Neat1 |
↓ |
↓ |
↓ VEGFA |
Subfertile |
[119] |
|
Nr5a2 (Lrh1) |
↓ |
↓ |
↓ VEGFA |
Infertile |
[120, 121] |
|
Plasminogen |
↓ |
Unaffected |
Unaffected |
n.d. |
[122] |
|
Prolactin |
↓ |
↓ VE-cadherin |
Infertile |
[123, 124] |
|
|
Scavenger receptor-B1 (SCARB1) |
↓ |
n.d. |
No effect |
n.d. |
[125] |
|
Superoxide dismutase (SOD1) |
↓ |
↓ |
↓ Vasculature |
Infertile |
[126] |
|
Tissue inhibitor of metalloproteinase 1 (TIMP1) |
↓ |
n.d. |
n.d. |
n.d. |
[127] |
|
Transforming growth factor-B1 (TGFB1) |
↓ |
↓ |
n.d. |
Infertile |
[128] |
n.d. not determined
The formation of the CL is a truly remarkable biological process with numerous and integrated events occurring in a relatively short timeframe, including (1) the luteinization/differentiation of granulosa and theca cells into luteal cells; (2) a steroidogenesis shift from estradiol to progesterone production that is accompanied with a massive upregulation in steroidogenic output (up to 1000 fold in the cow); (3) extensive remodeling, intermingling of cells (particularly in ruminants), and proliferation of the follicular tissue into a fully developed CL [5]. The bovine CL undergoes rapid growth (Fig. 1.1a), developing from less than 5 mm in size at ovulation to more than 20 mm within 10 days; this equates to a 60- to 100-fold increase in cellular volume, and the luteal growth rate is only matched by the fastest growing tumors [6]. Intriguingly, in the cow the postovulatory rise in progesterone lags behind the growth of the CL by 2–3 days (Fig. 1.1a). It has been speculated that the relatively slower rise in progesterone in ruminants compared to primates might be related to differences in luteal tissue remodeling and vascularization processes [7]. All these processes are totally dependent on intense angiogenesis, or formation of new blood vessels. This intensity is exemplified by the 15-fold increase in the total luteal volume of endothelial cells (EC) during formation of a mature bovine CL (Fig. 1.1b). Not surprisingly, the majority of the proliferating cells in the early CL are of vascular origin, with proliferation indices greater than 25 % [8, 9].
Fig. 1.1
Relationship between corpus luteum (CL) growth, plasma progesterone concentrations , and vasculature in the developing bovine corpus luteum. (A) Rapid increase in CL size after ovulation as determined by transrectal ultrasonography (n = 15). There is a similar increase in plasma progesterone concentrations, but this is initiated 2–3 days later compared to CL growth. (B) Tenfold increase in total luteal vasculature (EC; von Willebrand factor immunohistochemistry) during the formation of the CL (P < 0.01). There is a similar pattern of increase in the total area covered by pericytes (PC: smooth muscle actin immunohistochemistry). Data adapted from references [8, 114]
1.2 Follicular Programming of Luteal Angiogenesis
1.2.1 Preovulatory Follicular Vascular “Seed”
The structural and functional framework for CL development is provided by the preovulatory follicle, which leads to the concept of follicular programming of luteal function [5, 10, 11]. Although less is known about the role of follicular vascularization in this programming, it is entirely feasible that the degree of vascularization within the theca layer of the follicle could determine the rate of subsequent luteal vascularization. It has been proposed that during the follicle–luteal transition endothelial cells form ‘vascular initiation points .’ These points then create a scaffold from which endothelial cells can migrate and proliferate during the reconstruction of the vascular bed [7, 12]. As technologies for measuring microvascular blood flow develop, it will be important to determine the association between follicular vascularization and subsequent luteal function.
The second likely role of the preovulatory follicle in luteal angiogenesis is the active accumulation during folliculogenesis of various pro-angiogenic growth factors [e.g., fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor-A (VEGFA)]. Typically, concentrations of these factors in follicular fluid reach 1 ng/ml for FGF2 [13] and 2–5 ng/ml for VEGFA [14, 15]. It is further likely that these factors are sequestered (e.g., by perlecan) within the follicular basement membrane through their heparin-binding properties [16] and are released following the LH surge-induced activation of proteases during ovulation [17]. Indeed, addition of human follicular fluid to human umbilical vein endothelial cells (HUVECs) dose-dependently increased EC proliferation [18]. Intriguingly, however, heat inactivation or immuno-neutralization of FGF2/VEGFA failed to block this stimulation. Further experiments revealed that the mediator of follicular fluid-induced angiogenesis was the lipid molecule sphingosine-1-phosphate [18]. An alternative candidate is the biologically active phospholipid, lysophosphatidic acid (LPA) , which is produced by granulosa cells and is present in greater concentration in follicular fluid (up to 25 μM) compared to serum (~0.6 μM) [19]. Moreover, 10 μM LPA-treated granulosa-lutein-conditioned media stimulated migration, permeability, and proliferation of HUVECs, and this was mediated through increased interleukin (IL)-6 and -8 production [20]. LPA has also been shown to increase bovine aortic endothelial cell proliferation as well as progesterone production by bovine luteal cells [21].
1.2.2 Initiation by the LH Surge
The LH surge, as well as stimulating the ovulatory process, is also crucial in the upregulation of a plethora of genes, many of which are involved in regulating angiogenesis. Indeed, the size of the endogenous LH surge was positively associated with the degree of luteal vascularization in the developing CL [5]. Hence, the LH surge is often considered to initiate luteal angiogenesis [5]. For example, follicular FGF2 mRNA and protein concentrations are dramatically increased shortly after the LH surge in cows [13, 22, 23]. However, VEGFA expression appears to be less affected by the LH surge [13, 24]. It is still unclear as to the exact effect of the LH surge on VEGFA expression in luteinizing granulosa cells of other species, with some reports of significant stimulation [25, 26], whereas others reported decreased expression [27, 28].
The development of next-generation sequencing has enabled detailed profiling of the effect of the LH surge on the follicular transcriptome. Ingenuity pathway analysis has revealed that the expression of a number of angiogenesis-related genes are regulated by the LH surge: a summary of these genes is shown in Table 1.2. This approach has confirmed several factors already known to stimulate the angiogenic process and/or endothelial cell function (e.g., FGF2, fibronectin, and ephrin B2). It has also revealed several genes associated with tissue remodeling that also affect angiogenesis (e.g., secreted acidic cysteine-rich glycoprotein and transforming growth factor-β1), discussed later. The final and surprising observation was the identity of several upregulated factors classically considered as anti-angiogenic factors (e.g., pentraxin 3, semaphorin 3A/C, thrombospondin 1). It is feasible that this reflects a suppression of angiogenesis in the immediate post-LH surge period that is important until after ovulation has occurred.
Table 1.2
Identification of key angiogenesis-related genes by transcriptomic analyses that are affected by luteinizing hormone (LH) surge/gonadotropin stimulation
|
Gene |
Gene name |
Fold change |
Function |
Reference |
|
ADAM10 |
ADAM metallopeptidase domain 10 |
↑ 2.5-fold (b; GC/TC) |
Cleaves VE-cadherin, enabling EC migration and increasing vasculature permeability |
[129] |
|
ADAMTS1 |
ADAM metallopeptidase with thrombospondin type 1 motif; 1 |
↑ (m) ↑ 9-fold (b) |
Cleaves versican and aggrecan, enabling EC invasion |
[52, 78] |
|
ANGPT1 |
Angiopoietin 1 |
↑ 3-fold (h) |
Promotes vascular stabilization |
[28] |
|
CD24 |
CD24 molecule |
↑ 80-fold (h) |
Pro-angiogenic, and promotes cell invasion |
[28] |
|
CD36 |
CD36 molecule |
↑ 3-fold |
Thrombospondin receptor |
[129] |
|
EFNB2 |
Ephrin B2 |
↑ 16-fold (h) |
Regulates cell adhesion and migration during angiogenesis |
[28] |
|
FGF2 |
Fibroblast growth factor 2 |
↑ 22-fold (b) |
Promotes EC proliferation, migration, and sprouting |
[22] |
|
FN1 |
Fibronectin 1 |
↑ 5-fold (m) ↑ 3-fold (b) ↑ 5-fold (h) |
Component of ECM that promotes EC migration and proliferation |
[28, 52, 78] |
|
ITGA5 |
Integrin, alpha 5 |
↑ 10-fold (h) |
Adhesion molecule; acts as the fibronectin receptor |
[28] |
|
IGFB1 |
Integrin, beta 1 |
↑ 6-fold (m) |
Adhesion molecule; acts as fibronectin receptor |
[52] |
|
PTX3 |
Pentraxin 3 |
↑ 700-fold (b) |
Inhibitor of angiogenesis |
[78] |
|
PDGFBB |
Platelet-derived growth factor BB |
Upstream regulator |
Expressed in EC tip cells and stimulates pericyte recruitment |
[130] |
|
SEMA3A/C |
Semaphorin 3A and 3C |
↑ 16-fold (h) |
Anti-angiogenic and induces EC apoptosis |
[28] |
|
SPARC |
Secreted acidic cysteine-rich glycoprotein |
↑ 7-fold (m) |
Pro- and anti-angiogenic properties |
[52] |
|
THBS2 |
Thrombospondin 2 |
↑ 10-fold (b, GC) ↑ 5-fold (b, TC) |
Potent inhibitor of angiogenesis/VEGFA; inhibits EC proliferation and migration; Induces EC apoptosis |
[78] |
|
TGFB1 |
Transforming growth factor-B1 |
↑ 6-fold (h) Upstream regulator |
Pro- and anti-angiogenic properties |
[28] |
|
VEGFA |
Vascular endothelial growth factor-A |
↓ 2-fold (h) |
Pro-angiogenic |
[28] |
It should be noted that the different studies have collected tissue at different times relative to the LH surge, ranging from 1 to 36 h depending on the study design. Species: b bovine, h human, m mouse; cell type: GC granulosa cell, TC theca cell, EC endothelial cell
Ovulation requires the production of prostaglandins (PG), and treatment with cyclooxygenase-2 (COX-2) inhibitors impairs ovulation [29]. The synthesis of prostaglandins from the granulosa cells is upregulated by the LH surge, reaching peak concentrations just before ovulation [30, 31], and PGE2 has been identified as the key ovulatory prostaglandin, at least in primates [32]. There is increasing evidence that PGE2 is not only crucial for ovulation but that it is also an important stimulator of luteal angiogenesis. Sakurai et al. [33] showed that treatment of rats with the COX-2 inhibitor NS-398 suppressed the formation of luteal vasculature in the newly formed CL as well as decreasing progesterone production. Furthermore, the coadministration of PGE2 reversed this effect. It is likely that PGE2 is acting through the PGE type 2 receptor (PTGER2) , because the PTGER2 antagonist AH6809 suppressed luteal EC tube formation in rats [34]. The PTGER1-4 co-localized with EC within the luteinising granulosa layer 36 h after hCG treatment in primates [32]. Furthermore, intrafollicular injection of PTGER1 and PTGER2 agonists promoted vascularization of the luteinizing granulosa layer, via stimulating branching angiogenesis [32]. An additional complexity is the potential interplay between PGE2 and the key pro-angiogenic growth factors FGF2 [35] and VEGFA [34]; this concept warrants further investigation.
1.3 Control of Luteal Angiogenesis
1.3.1 Local Regulation of Luteal Angiogenesis
1.3.1.1 Fibroblast Growth Factor-2 and Vascular Endothelial Growth Factor-A
Luteal angiogenesis requires the highly coordinated and orchestrated interplay between endothelial and steroidogenic cells as well as fibroblasts and pericytes to create an extensive and complex vascular network that is absolutely essential for luteal function. The best characterized pro-angiogenic regulators of luteal angiogenesis are FGF2 and VEGFA, which are both potent mitogens of vascular endothelial cells (EC) as well as stimulating EC migration and survival. FGF2 is a more potent stimulator of luteal EC proliferation than VEGFA [36], whereas VEGFA also induces vascular permeability [37, 38]. The critical importance of VEGFA for luteal angiogenesis is emphasized in studies where inhibition of VEGFA action massively reduced luteal vascularization and progesterone production in primates [2].
In the developing CL, VEGFA protein is localized predominantly to steroidogenic cells in cows [39] and humans [40], and this is thought to direct angiogenesis toward the hormone-producing cell [41]. Intriguingly, in the very early CL, there are transiently very high levels of FGF2, which return within a few days to basal levels [13, 36]. At the same time, FGF2 protein localization shifts from EC to steroidogenic cells and back again [23], which led us to speculate that FGF2 has a dynamic role in the initiation of luteal angiogenesis in the cow [5].
We have further dissected the function of FGF2 and VEGFA in regulating bovine luteal angiogenesis using a physiologically relevant in vitro system in which multiple luteal cell types (steroidogenic cells, ECs, fibroblasts, pericytes) isolated from a recently ovulated CL are co-cultured in a specialized EC media [42]. Importantly, in this system EC form an intricate network, and the degree of network formation is highly responsive to angiogenic stimuli [42, 43]. Image analysis of these EC networks revealed that there are multiple branch points and interconnections that develop with time in culture [44, 45]. Simultaneously, progesterone production increases over time, and this is responsive to an LH challenge.
The formation of EC networks was suppressed with the addition of specific VEGF receptor (VEGFR) and FGF receptor (FGFR) inhibitors, with EC appearing most sensitive to FGFR inhibition [43]. Using a different approach, the treatment of bovine luteal cells with either FGF2 or VEGFA antibody more or less completely inhibited the formation of EC networks, even when the other angiogenic factor was present (Fig. 1.2). Similarly, FGF2-induced EC proliferation and migration were inhibited by treatment of bovine luteal cells with small molecule 27 (a fragment of thrombospondin that sequesters FGF2) [36]. Further investigation revealed that EC were most sensitive to FGFR inhibition during the time in which islands of EC are starting to sprout/branch [45]. More importantly, FGF2 promoted the precocious transition of undeveloped EC islands into organized EC networks, which was associated with an increased number of EC branch points [44]. The crucial process for EC sprouting is the formation of a specialized EC tip cell within the established vasculature that is capable of migrating toward the angiogenic stimulus. Thus, it is likely that FGFR signaling is crucial for endothelial tip cell formation and vascular sprouting [46]. However, knowledge is still limited about the way FGF2 induces EC tip cells. The effects of intraluteal infusion of FGF2 post ovulation on luteal vasculature and function in vivo certainly warrant investigation.
Fig. 1.2
Effect of immuno-neutralization of FGF2 and VEGFA on luteal endothelial cell (EC) networks in a physiologically relevant culture system that mimics luteal bovine angiogenesis and function. Dispersed bovine luteal cells were cultured on fibronectin-coated wells in specialized EC media for 9 days. Immunohistochemistry for von Willebrand factor was performed to identify the EC. (A) Bovine luteal cells treated with control showed extensive EC networks/islands (brown staining, arrows) that resembled a capillary bed. (B) Bovine luteal cells treated with VEGFA antibody at (Ab) 1:2000 dilution. Some reduced EC networks are present. Bovine luteal cells treated with FGF2 antibody at 1:2000 (C) and 1:20,000 (D) had no EC networks. However, there was extensive proliferation of other cell types. Bars 100 μm
The regulation of vascular permeability is a key function of the endothelial cell and is important in the supply of nutrients/hormones to the luteal tissue. As mentioned earlier, VEGFA is a potent stimulator of EC permeability, which is controlled by adherens (e.g., VE-cadherin) and tight junctions (e.g., claudins). Herr et al. [47] showed that hCG induced a VEGFA-dependent downregulation of VE-cadherin and claudin 5 expression, which was associated with increased endothelial cell permeability in a human granulosa-endothelial co-culture system. Additionally, treatment of marmoset monkeys with VEGFA Trap during the mid-luteal phase increased the degree of claudin 5 staining in the CL [48].
1.3.1.2 Interleukins
Interleukin 8 (IL-8) is a neutrophil-specific chemoattractant and pro-angiogenic cytokine that is highly expressed in the early CL, coincident with the abundance of polymorphonuclear neutrophils (PMNs). Moreover, conditioned media from culture of early luteal cells, but not those from a mid-luteal phase CL, stimulated PMN migration in vitro that was blocked with an IL-8 antibody. Importantly, recombinant bovine IL-8 as well as PMN supernatant stimulated luteal EC proliferation and tube formation in vitro [49]. However, Talbott et al. [50] found that IL-8 had no effect on purified luteal endothelial cells derived from early pregnant CL. It is feasible that there is interplay with lysophosphatidic acid (LPA) and IL-8 as LPA induced IL-8 expression in granulosa-lutein cells [20].
1.3.1.3 Secreted Protein Acidic Rich in Cysteine (SPARC)
SPARC is a matrix-associated glycoprotein that regulates cell differentiation, migration, and cell–cell communication. Importantly, the function of SPARC is changed by targeted proteolytic degradation, with the mature SPARC protein being anti-angiogenic and its proteolytic fragments generally being pro-angiogenic [51]. Transcriptomic analysis of hCG-regulated genes in murine granulosa cells revealed that SPARC mRNA was upregulated sevenfold by hCG [52]. The precocious expression of SPARC was dose-dependently induced by transforming growth factor-beta (TGFβ) and fibronectin in bovine luteinizing granulosa cells [53]. Furthermore, SPARC protein expression was abundantly present in luteal and endothelial cells of the developing bovine CL [13, 54]. Functionally, a plasmin proteolytic fragment of SPARC (KGHK) increased EC network formation in vitro and also stimulated progesterone production (to a greater extent than LH) in bovine luteal cells [53]. Thus, SPARC or KGHK-containing peptides could be novel targets for the treatment of luteal inadequacy.
1.3.1.4 Hypoxia
A key driver of angiogenesis during tumor development is the hypoxia-induced upregulation of VEGFA. Cells respond to hypoxia through the activation of hypoxia-inducible factor 1 (HIF1), which is a transcription factor that binds to hypoxia response elements (HRE) in the promoter region of hypoxia-regulated genes. HIF1 is a heterodimer consisting of the oxygen-regulated HIF1A and the constitutively expressed HIF1B [55]. Oxygen concentrations in follicular fluid decrease in the latter stages of antral follicle development [56]. The remodeling of vasculature at ovulation and during early luteal development lowers tissue oxygen concentrations and therefore higher HIF1A would be expected. Indeed, HIF1A is upregulated around the ovulatory period in pigs [57], humans [58], cows [59], and mice [60]. Moreover, echinomycin, a small molecular inhibitor of HIF1 binding to HRE, blocked ovulation in mice [26]. Culturing luteal cells in hypoxic conditions (2–3 % O2) or chemically induced hypoxia increases HIF1A expression and VEGFA [59, 60]. There is also some evidence that hCG/LH directly upregulates HIF1A in granulosa-lutein cells [25, 60]. The relationship between hypoxia and FGF2 expression remains largely unknown. In HUVECs, hypoxic conditions increased FGF2-induced proliferation and tube formation in comparison to normoxia [55]. The exact function of hypoxia in regulating luteal angiogenesis and EC network formation remains to be elucidated.
1.3.1.5 Notch System
The Notch signaling pathway plays an integral role in EC tip formation with the membrane-bound delta-like ligand 4 (DLL4) being expressed in tip cells [61]. When DLL4 binds to its receptor, Notch, on adjoining EC, it converts them into stalk cells [62]. DLL4 and Notch1–4 have been detected in endothelial and steroidogenic cells of developing CL in mice [63, 64]. In mice, treatment with a γ-secretase inhibitor (to block downstream Notch signaling) impaired preovulatory follicle development: this was associated with the theca layer having a disorganized EC framework and an increased vascular smooth muscle cell density. Furthermore, plasma estradiol concentrations were nearly threefold lower [65]. In the same model, treatment with a DLL4-blocking antibody had minimal effects on follicular appearance, although in marmosets, inhibition of DLL4 during the periovulatory period caused the CL to be hypervascularized and decreased progesterone production [66]. This EC patterning has several similarities to that induced by high concentrations of FGF2 in bovine luteal cells [44]. Recent observations showed that the treatment of luteal cells with a γ-secretase inhibitor reduced progesterone concentrations in rats [67]. The potential interplay between FGF2, VEGFA, and the Notch system warrants investigation.
1.3.2 Role of Anti-Angiogenic Factors
1.3.2.1 Thrombospondin (THBS)
Thrombospondin-1 and -2 are large glycoproteins secreted by several cell types that bind to the extracellular matrix (ECM). THBS, acting through its receptor CD36, regulates several processes in EC including migration, adhesion, and apoptosis. Contrary to expectation, the expression of THBS1, THBS2, and CD36 was greatest during the early luteal phase in rats [68, 69]. FGF2 and THBS1 had opposing actions on bovine luteal EC in vitro, with THBS1 reducing cell numbers by inducing EC apoptosis [70]. Furthermore, THBS1 inhibited FGF2-induced luteal EC migration and proliferation [36] and THBS/FGF2 downregulate the opposing gene [70]. These in vitro observations are in agreement with the effect of the thrombospondin-mimetic peptide, ABT898 , on follicular angiogenesis in marmoset monkeys [71]. However, in the same study ABT898 had no effect on ovulation or plasma progesterone concentrations [71].
1.3.2.2 Vascular Endothelial Growth Factor A : ‘b’ Isoform
The alternative splicing of exon 8 in the VEGFA gene yields two different families of VEGFA isoforms. The first family is the classic pro-angiogenic isoform with exon 8a, and the other is the anti-angiogenic isoform with exon 8b present. This isoform is termed VEGFAxxxb [72]. Relatively little is known about this additional complexity, and most VEGFA antibodies do not distinguish between these two different isoform families. Recently, it was reported that the VEGFA120b isoform was expressed in parallel to VEGFA120a, with expression increasing with CL age, whereas VEGFA164b was not detected in the ovine CL [73]. Importantly, mice overexpressing VEGFA164b had reduced fertility, CL number, and degree of vascularization within the CL [74], further emphasizing the importance of the balance between pro- and anti-angiogenic growth factors during luteal development.
1.3.2.3 Vasohibin 1
Vasohibin 1 (VASH1) and IGF-binding protein 7 (IGFBP7) are another two recently identified negative feedback regulators of vascularization. VASH1 is constantly expressed throughout bovine luteal development in luteal endothelial cells, and its expression is upregulated by VEGFA [75]. In the cow, VASH1 suppressed VEGFA-induced luteal EC tube formation [75], suggesting that it could prevent overstimulation of angiogenesis. The high-affinity insulin, low-affinity IGF1-binding protein, IGFBP7, regulates cell proliferation, adhesion, and angiogenesis. It has been detected in the follicular fluid and corpora lutea of rats [76], but to date has not been reported in other species. Recently, IGFBP7 (at 160 ng/ml) was shown to reduce VEGFA- and LH-stimulated luteal EC tube formation, but it had no effect under basal conditions [77]. Lower concentrations of IGFBP7 had no effect [77], and the physiological role of IGFBP7 in regulating luteal angiogenesis remains to be determined.
1.3.2.4 Pentraxin 3
Pentraxin 3 (PTX3) is a 45-kDa glycosylated protein that is produced by endothelial cells and activated phagocytes. It is known to bind FGF2 with a high affinity and thus prevents FGF2 from binding to FGFR, blocking its angiogenic actions [37]. The massive upregulation of PTX3 in bovine granulosa cells following the LH surge [78] shortly before a period of intense angiogenesis seems counterintuitive, especially because PTX3 inhibited FGF2 action on bovine luteal ECs [36]. Interestingly, PTX3 expression is greatly increased in the mature CL following PGF2α administration , suggesting that PTX3 has an anti-angiogenic function in luteolysis [36].
1.4 Establishment of Luteal Vasculature
1.4.1 VE-Cadherin
VE-cadherin is an endothelial-specific molecule that forms adherens junctions between adjacent endothelial cells. VE-cadherin not only maintains vascular integrity but also regulates cellular processes such as EC proliferation, apoptosis, and VEGFR function [79]. It was recently discovered that Notch/VEGFR signaling alters the dynamics of VE-cadherin junctions that drive endothelial rearrangements during sprouting [80]. The immuno-neutralization of VE-cadherin with E4G10 antibody in mice reduced CL development, degree of vascularization, and plasma progesterone concentrations [81], highlighting the critical importance of VE-cadherin for luteal angiogenesis. Treatment of bovine CLENDO cells with TGFB1 caused the loss of VE-cadherin from cell junctions, reduced cell–cell contacts, and increased EC permeability [82]. Conversely, FGF2 signaling promotes VE-cadherin expression and maintains vascular integrity [83].
1.4.2 Pericytes
Pericytes (mural cells) form intimate contacts with endothelial cells and are an integral component of the microvasculature. Classically, pericytes are considered to be involved in the latter stages of angiogenesis by stabilizing newly formed EC tubes. It is increasingly evident that pericytes are also active in the early stages of angiogenesis [84]. The induction of platelet-derived growth factor receptor-B (PDGFRB) expression activates pericytes and stimulates their recruitment to endothelial cells. Indeed, intraovarian PDGFR blockade reduced the number of CL and progesterone production [85, 86] as well reducing the microvessel EC density by nearly 50 %, as well as pericyte coverage of those vessels [86]. It has been observed that pericytes appear to migrate into the luteinizing-granulosa layer “ahead” of EC in the developing sheep [87] and cattle CL [7, 88]. Furthermore, in the developing CL, pericytes are in abundance (Fig. 1.1b) and form a large proportion of proliferating cells [87]. Pericytes could have several functions to support the intense luteal angiogenesis, including (1) laying down fibronectin strands along which EC can migrate [7]; (2) increased migratory phenotype through the suppression of contractile vascular smooth muscle cell [89]; and (3) making multiple contacts between EC that assist with their stabilization and thus co-ordinating the luteal vascularization. This idea is supported by the observation that smooth muscle actin (SMA) -positive mural cells are often localized in close proximity to EC islands and are often an integral component of these islands [5]. Furthermore, one particular mural phenotype has several finger-like projections that connect to EC and other mural cells [5]. Importantly, Woad et al. [43] demonstrated that in vitro PDGFRB blockade with a receptor tyrosine kinase inhibitor greatly attenuated the ability of EC to develop into networks with the earliest stages most sensitive to PDGFRB inhibition.
1.4.3 Insulin-Like Growth Factor (IGF) System
Insulin-like growth factor-1 (IGF1) is a well-established endocrine and paracrine growth factor that is known to be important in regulating follicular and luteal function. IGF1 is locally expressed in the CL [90] and has a stimulatory effect on progesterone secretion [91]. It is also known to have pro-angiogenic properties [92, 93], particularly in respect to developmental angiogenesis and neovascularization [94]. Recent evidence has shown that IGF1 promotes angiogenesis by stabilizing endothelial cell tubes and nascent blood vessels in the retina in response to VEGFA [95]. The latter might be particularly important for luteal angiogenesis because the neovascularization of the CL initially involves the destabilization of the vasculature within the theca layer. Knowledge is limited about the role of IGF1 in regulating ovarian angiogenesis; however, IGF1 decreased thrombospondin 1 expression in porcine granulosa cells [96].
1.5 Clinical Opportunities
Appropriate vascularization is critical to normal ovarian function. Dysregulated vascular growth has been implicated in the origin or development of several ovarian pathologies and is therefore a promising target for the treatment of disease.
1.5.1 Ovarian Cancer
Ovarian cancer , primarily epithelial in type, is a leading cause of female cancer death and the most aggressive of the gynecological cancers. More than 200,000 women develop epithelial ovarian cancer worldwide each year, with most cases diagnosed in women over 55 years of age. It is characterized by a high death rate, largely attributed to the late presentation of many cases and hence associated metastatic disease. Most cases of advanced disease also recur, with disease-free intervals becoming progressively shorter [97]. Standard clinical management is by surgery and platinum-based cytotoxic chemotherapy; however, new therapeutic strategies are emerging, including anti-angiogenic treatment [98].
Tumor blood vessels exhibit multiple abnormalities of structure and function and are especially dynamic [99]. Tumor growth and eventual metastasis require active angiogenesis, resulting from both the upregulation of pro-angiogenic factors and downregulation of endogenous inhibitors, thereby presenting multiple opportunities for therapeutic intervention.
Advanced epithelial ovarian carcinoma is associated with raised serum VEGFA levels [100], and VEGFA has been the primary therapeutic target to date: approaches include using antibodies against VEGFA or VEGFR, soluble decoy receptors (VEGF Trap), or VEGFR tyrosine kinase inhibitors. Phase 3 trials have demonstrated increased progression-free survival in women with ovarian cancer treated with VEGF inhibition (bevacizumab) in addition to standard chemotherapy [101, 102]. The benefit of anti-VEGFA therapy was evident as first-line treatment, maintenance therapy, or at recurrence, although the impact on overall survival is less clear. Further advances are expected in the use of multi-angiokinase inhibitors that target tumor angiogenesis at multiple levels, for example, via combined VEGF, FGF, and PDGF signaling inhibition [103, 104].
Another promising target is the angiopoietin/Tie2 pathway [105, 106]. Treatment with Trebananib (AMG 386), which binds Angpt1 and -2, thereby preventing Tie2 activation, prolonged progression-free survival in women with ovarian cancer [107]. Opportunities to exploit the endogenous inhibition of angiogenesis are also being explored. For example, thrombospondin-mediated inhibition of angiogenesis enhanced the clinical effectiveness of chemotherapy in a mouse model of ovarian cancer by altering vascular morphology, facilitating drug uptake, and increasing apoptotic cell death [108].
1.5.2 Ovarian Hyperstimulation Syndrome
Ovarian hyperstimulation syndrome (OHSS) is a rare but potentially life-threatening complication of ovarian stimulation for fertility treatment. It occurs during the luteal phase or early pregnancy [109] and is characterized by a systemic increase in vascular permeability, thought to result from the ovarian secretion of vasoactive peptides such as VEGFA. VEGFA is implicated because of an association of OHSS with raised luteal and follicular fluid VEGFA expression and bioavailability [110] and the stimulation of vascular permeability in response to VEGFA [111]. Despite the potential importance of VEGFA in mediating OHSS, targeting VEGFA directly led to undesirable side effects in animal models, and hence most preventative treatments have targeted the stimulation protocol itself, such as reducing the duration of the LH surge. An attractive alternative clinical strategy to reduce the incidence and severity of OHSS is the use of dopamine agonists acting as VEGF inhibitors [112]. Treatment of high-risk women with dopamine agonists lowered the incidence of OHSS without detrimental effects on implantation or pregnancy outcome following assisted reproduction [113], despite the clear need for ovarian and endometrial angiogenesis.
1.6 Conclusion
Angiogenesis is critical to support the dramatic growth and development of the CL. Although VEGFA and FGF2 may be seen as the primary regulators of luteal angiogenesis, it is increasingly evident that numerous other factors are expressed by several luteal cell types and that these also have important modulatory functions. Transcriptomic studies are shedding new light on the complexities of luteal angiogenesis at the molecular level, and a better understanding of the control of luteal angiogenesis will also highlight potential new therapeutic opportunities to tackle angiogenesis-dependant ovarian disease.
Acknowledgments
This work has been funded by BBSRC, Pfizer and University of Nottingham. We greatly appreciate the technical assistance of staff at the University of Nottingham without which this work would not have been possible.
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