Hypocoagulable State of Human Preovulatory Ovarian Follicular Fluid: Role of Sulfated Proteoglycan and Tissue Factor Pathway Inhibitor in the Fluid1

Shimada, Hayato; Kasakura, S; Shiotani, Masahide; Nakamura, Kimihiko; Ikeuchi, M; Hoshino, Tatsuji; Komatsu, Takayuki; Ihara, Yoshiyuki; Sohma, M.; Maeda, Yukihide; Matsuura, Ryoichiro; Nakamura, Shin; Hine, Chiemi; Ohkura, Naoki; Kato, Harubumi

doi:10.1095/biolreprod64.6.1739

Cited by 25 publications

(24 citation statements)

References 35 publications

(47 reference statements)

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“…The levels in hFF of some clotting factors such as Factor V and fibrinogen were decreased in hFF to 4.0 -10% and to 13-25% of their respective plasma concentrations (Table 1). These data are in keeping with previous observations (14,15). The PT, aPTT, and TT were markedly prolonged.…”

Section: Hff Contains a Potent Anticoagulant Activitysupporting

confidence: 93%

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Human Follicular Fluid Heparan Sulfate Contains Abundant 3-O-Sulfated Chains with Anticoagulant Activity

Agostini

Dong

Arrighi

et al. 2008

Journal of Biological Chemistry

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Anticoagulant heparan sulfate proteoglycans bind and activate antithrombin by virtue of a specific 3-O-sulfated pentasaccharide. They not only occur in the vascular wall but also in extravascular tissues, such as the ovary, where their functions remain unknown. The rupture of the ovarian follicle at ovulation is one of the most striking examples of tissue remodeling in adult mammals. It involves tightly controlled inflammation, proteolysis, and fibrin deposition. We hypothesized that ovarian heparan sulfates may modulate these processes through interactions with effector proteins. Our previous work has shown that anticoagulant heparan sulfates are synthesized by rodent ovarian granulosa cells, and we now have set out to characterize heparan sulfates from human follicular fluid. Here we report the first anticoagulant heparan sulfate purified from a natural human extravascular source. Heparan sulfate chains were fractionated according to their affinity for antithrombin, and their structure was analyzed by 1 H NMR and MS/MS. We find that human follicular fluid is a rich source of anticoagulant heparan sulfate, comprising 50.4% of total heparan sulfate. These antithrombin-binding chains contain more than 6% 3-Osulfated glucosamine residues, convey an anticoagulant activity of 2.5 IU/ml to human follicular fluid, and have an anti-Factor Xa specific activity of 167 IU/mg. The heparan sulfate chains that do not bind antithrombin surprisingly exhibit an extremely high content in 3-O-sulfated glucosamine residues, which suggest that they may exhibit biological activities through interactions with other proteins.Follicular fluid contains components of the coagulation cascade and subsequent to ovulation undergoes clotting within the ruptured follicle. Yet the timing of this process must be tightly regulated as a liquid state must initially be maintained for the oocyte to be successfully delivered to the oviduct. Given the complexity of coagulation, there are likely multiple mechanisms to regulate clotting of follicular fluid. One such mechanism could involve heparan sulfate proteoglycans (HSPGs). 2HSPGs are ubiquitously distributed on the surface of animal cells and are secreted into the extracellular environment. They have numerous important biological activities mediated through interactions with diverse proteins. HSPGs are composed of a core protein with covalently attached HS chains formed by repetitive sulfated disaccharides of uronic acid and glucosamine. The different length and variable sequence of sulfated disaccharides generate the structural diversity required to form specific oligosaccharide-binding sites for proteins such as growth factors, protease inhibitors, or cell adhesion molecules. The reactivity of proteins is affected by their binding to HS. This principle is exemplified by heparin and anticoagulant HS (aHS), which bind to antithrombin (AT) and thereby accelerate the rate at which AT inhibits serine proteases in the bloodclotting cascade.The AT-binding pentasaccharide of heparin and aHS proteoglycans ...

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Section: Hff Contains a Potent Anticoagulant Activitysupporting

confidence: 93%

“…Compared with plasma, hFF contains high levels of tissue factor pathway inhibitor, which may limit initiation of coagulation (15). Similarly, hFF contains low concentrations of Factors V and VIII (15, 31), which might limit amplification of thrombin formation (32).…”

Section: Discussionmentioning

confidence: 99%

Human Follicular Fluid Heparan Sulfate Contains Abundant 3-O-Sulfated Chains with Anticoagulant Activity

Agostini

Dong

Arrighi

et al. 2008

Journal of Biological Chemistry

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“…1984, Grimek et al 1984, Reyes et al 1984, Bushmeyer et al 1985, Bellin et al 1986, 1987, Bellin & Ax 1987, Sato et al 1987, Tsuiki et al 1988, Vanderboom et al 1989, Varner et al 1991, Andrade-Gordon et al 1992, Wise & Maurer 1994, Boushehri et al 1996, Parillo et al 1998, Shimada et al 2001) and this study demonstrates that they contribute to the osmotic potential of follicular fluid and are at sizes too large to leave the follicular antrum. Hyaluronan has a variety of physiological functions in the extracellular matrix, such as rheological properties, flow resistance, osmotic pressure, exclusion properties and filter effects.…”

Section: Discussionmentioning

confidence: 58%

Formation of ovarian follicular fluid may be due to the osmotic potential of large glycosaminoglycans and proteoglycans

Clarke¹,

Hope²,

Byers³

et al. 2006

Reproduction

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During mammalian follicle development, a fluid-filled antrum develops in the avascular centre of the follicle. We investigated the hypothesis that follicular fluid contains osmotically-active molecules, sufficiently large so as to not freely escape the follicular fluid. Such molecules could generate an osmotic differential and thus recruit fluid from the surrounding vascularised stroma into the antrum. Follicular fluid was collected from bovine follicles classified histologically as healthy (nZ4 pools) or atretic (nZ4 pools). Dialysis of the follicular fluid at 300 kDa or 500 kDa resulted in a reduction in colloid osmotic pressure of 35% and 60%, respectively, in fluid from healthy follicles and 29% and 80% from atretic follicles. Digestion of follicular fluid with Streptomyces hyaluronidase, chondroitinase ABC or DNase 1 followed by dialysis resulted in reductions in osmotic pressure of 43%, 53% and 43% respectively for fluids from healthy follicles and 34%, 20% and 31% for atretic follicles. Digestion with collagenase I, proteinase K, heparanase 1 or keratanase had no significant effect on the osmotic pressure of follicular fluid of healthy follicles. Ion exchange and size exclusion, Western blotting and ELISA identified the proteoglycans versican and inter-alpha trypsin inhibitor and the glycosaminoglycan hyaluronan in follicular fluid. We conclude that these molecules or aggregates of them are of sufficient size to contribute to the osmotic potential of follicular fluid and thus recruit fluid into the follicular antrum. DNA may also contribute but it is probably not a component that is regulated for this role.

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“…Human follicular fluid has greater anticoagulant activity than plasma, mostly likely because of a combination of heparan sulphate and antithrombin activity (Shimada et al 2001). Anticoagulant HS (aHS) contain a pentasaccharide sequence common to heparin.…”

Section: Heparan Sulphate Proteoglycansmentioning

confidence: 99%

Extracellular matrix in ovarian follicular development and disease

Irving-Rodgers

Rodgers

2005

Cell Tissue Res

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The ovarian follicle contains several different cell types and separate compartments and undergoes substantial development during its growth and maturation. Extracellular matrix (ECM) could be expected to play a major role in these processes. Most research on ECM in follicles has focused on the follicular basal lamina and its changing composition during folliculogenesis and on the specialised matrix formed at ovulation by the cumulus cells surrounding the oocyte and the zona pellucida. We review these aspects. Few naturally occurring gene mutations have identified unique roles for ECM molecules in follicular function. Presumably, any mutations leading to reduced fertility are eliminated quickly by natural selection and, when mutations are not eliminated, considerable redundancy occurs to ensure successful reproduction. In mice, in which the genome can be easily manipulated, the modification of matrix components associated with cumulus and oocytes has often resulted in partial infertility, suggesting redundancy. We provide an update of basal lamina components focusing on newer discoveries. In addition, we review matrix associated with the occyte and cumulus cells (excluding the zona pellucida) and other components of ECM. Where possible, we examine evidence for the role of the ECM in follicular development and diseases.

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Hypocoagulable State of Human Preovulatory Ovarian Follicular Fluid: Role of Sulfated Proteoglycan and Tissue Factor Pathway Inhibitor in the Fluid1

Cited by 25 publications

References 35 publications

Human Follicular Fluid Heparan Sulfate Contains Abundant 3-O-Sulfated Chains with Anticoagulant Activity

Human Follicular Fluid Heparan Sulfate Contains Abundant 3-O-Sulfated Chains with Anticoagulant Activity

Formation of ovarian follicular fluid may be due to the osmotic potential of large glycosaminoglycans and proteoglycans

Extracellular matrix in ovarian follicular development and disease

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