Modulation of Bone Marrow-Derived Endothelial Progenitor Cell Activity by Protein Tyrosine Phosphatases

Modulation of Bone Marrow-Derived Endothelial Progenitor Cell Activity by Protein Tyrosine Phosphatases Sébastien Trop 1 , Michel L. Tremblay, and Annie Bourdeau⁎

Adult bone marrow contains stem cells capable of reconstituting the vascular system. The ordered progression of stem cells and more differentiated endothelial precursor cells through successive developmental stages is tightly controlled. The specialized microenvironment of the bone marrow as well as cell-autonomous processes directs the renewal and differentiation of stem cells into endothelial cells. Tyrosine phosphorylation of receptors, adaptors, and structural proteins is one mechanism whereby endothelial cell development is regulated, which involves the opposing action of protein tyrosine kinases and phosphatases. The present review focuses on the role of four nontransmembrane protein tyrosine phosphatases (T cell protein tyrosine phosphatase [TCPTP], protein tyrosine phosphatase 1B [PTP1B], Scr homology phosphatase-1 [SHP-1], Scr homology phosphatase-2 [Shp-2]) in the selfrenewal, differentiation, mobilization, and homing of endothelial progenitor cells, as well as their ability to incorporate into nascent blood vessels. Endothelial progenitor cells are known to promote vasculogenesis, accelerating restoration of blood flow to ischemic tissues, and improve cardiac function after infarct. The use of protein tyrosine phosphatase inhibitors to modulate the development and function of endothelial progenitor cells as a potential novel therapy for peripheral vascular and coronary artery disease in humans is discussed. (Trends Cardiovasc Med 2008;18:180–186) n 2008, Elsevier Inc. 

Adult Vasculogenesis

Vasculogenesis refers to de novo formation of blood vessels from undifferen-

tiated precursor cells, termed endothelial progenitor cells (EPCs), and this process contributes to postnatal neovasculariza-

Sébastien Trop is at the Division of Cardiac Surgery, McGill University Health Center, McGill University, Montreal, QC, Canada. Michel L. Tremblay is at the McGill Cancer Centre, McGill University, Montreal, QC, Canada. Annie Bourdeau is at the McGill Cancer Centre, McGill University, Montreal, QC, Canada H3G 1Y6; Sunnybrook Health Sciences Centre, Toronto, ON, Canada M4N 3M5. ⁎ Address correspondence to: Annie Bourdeau, PhD, Sunnybrook Health Sciences

Centre, 2075 Bayview Avenue, S Wing, Room S227, Toronto, ON, Canada M4N 3M5. Tel.: (+416) 480 6100x3139; fax: (+416) 480 5703; e-mail: [email protected]. © 2008 Elsevier Inc. All rights reserved. 1050-1738/08/$-see front matter 1 Current address: Interdepartmental Division of Critical Care, University Health Network, University of Toronto, 585 University Avenue, 11C-1170 Toronto, ON, Canada M5G 2N2.

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tion (reviewed in Urbich and Dimmeler 2004). After vascular injury, a small percentage of EPC enters into the circulation. Circulating EPC (CEPC) is preferentially recruited to sites of ischemia and incorporated into the vessel structure to participate in vascular regeneration. An increased number of CEPC in experimental models correlated with stimulation of neovascularization in vivo (Heeschen et al. 2003). Thus, augmenting the local availability of EPC enhances this process. At the molecular level, the expansion and mobilization of bone marrow-derived EPC to the site of injury can be attributed to factors present within the microenvironment and to cellautonomous adaptation of the stem cell in response to ischemia. In humans, other factors affect the availability and regenerative potential of EPC for repair of vascular injury, including drugs such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (“statins”), the postsurgical state, and the presence of comorbid conditions, such as chronic myocardial ischemia (reviewed in Urbich et al. 2005). 

Hematopoietic and Endothelial Lineage Development Within the Bone Marrow

Apart from bone marrow stromal cells and their progeny, adult bone marrow contains cells of the hematopoietic and endothelial lineages, which originate from hematopoietic stem cells (HSCs) and EPC, respectively. Hematopoietic stem cells and EPCs are indistinguishable from each other by known surface markers (Figure 1). The existence of a common precursor, termed the hemangioblast, remains controversial but reflects the dual differentiation capacity of the more primitive stem cells into hematopoietic and endothelial lineage cells (Ribatti 2008). The developmental hierarchy in hematopoiesis is well defined and starts with long-term HSCs, giving rise to short-term HSCs that have limited selfrenewal capacity. Short-term HSCs can differentiate into committed common

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Figure 1. Hematopoietic and endothelial differentiation in adult bone marrow. Scheme representing cellular hierarchy in bone marrow hematopoiesis (left) and vasculogenesis (right). Cell surface markers that define each bone marrow cell subpopulation are indicated. LT-HSC indicates long-term HSC; ST-HSC, short-term HSC; CMP, common myeloid progenitor; CLP, common lymphoid progenitors; GMP, granulocyte– monocyte progenitors; MEP, megakaryocyte–erythrocyte progenitors; TEPC, tissue EPC.

myeloid progenitors or common lymphoid progenitors. Common lymphoid progenitors further differentiate into all lymphoid lineages, including T, B, and natural killer cells. Common myeloid progenitors give rise to granulocyte– monocyte progenitors, yielding mature monocytes and granulocytes, or to megakaryocyte–erythrocyte progenitors, which produce platelets and erythrocytes (Akashi 2005) (Figure 1). The developmental scheme of the endothelial lineage has

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been characterized more recently. From EPCs, CEPCs are produced, which can differentiate into tissue EPCs (Urbich and Dimmeler 2004). Alternatively, monocytes may also differentiate into tissue EPCs. Ultimately, these EPCs can differentiate into endothelial cells (ECs) (Khmelewski et al. 2004) (Figure 1), which have the ability to form capillary-like structures in vitro, and acquire mature EC markers such as CD31 (reviewed in Kawamoto and Losordo 2008).



Regulation of EPC Function in Postnatal Neovasculogenesis

In the adult, the formation of new blood vessels occurs mainly in response to injury, such as trauma or ischemia. Enhanced recruitment of EPC at the site of injury correlates with increased cytokine concentrations both locally and systemically (Asahara et al. 1999, Gill et al. 2001, Kong et al. 2004, Takahashi et al. 1999), and with the activation of

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signal transducers and activators of transcription (STAT) proteins, STAT1, STAT3, and STAT5 in cardiomyocytes, vascular smooth muscle cells, and hypoxic ECs, respectively (Dudley et al. 2005, Hilfiker-Kleiner et al. 2004, Seki et al. 2000). In humans, the number of circulating CD34+ stem cells is increased after treatment with granulocyte colonystimulating factor (G-CSF), as a result of enhanced mobilization and recruitment of EPC from the bone marrow (Dreger et al. 1994). When administered in combination with stromal cell-derived factor 1, G-CSF accelerates neovascularization and increases blood perfusion in a mouse model of hind limb ischemia (Tan et al. 2007). Another cytokine, granulocyte macrophage colony-stimulating factor (GM-CSF), was also shown to increase the number of circulating hematopoietic progenitors. In a small study of patients with sarcoma, administration of GM-CSF increased the number of granulocyte macrophage and erythroid colony-forming units in peripheral blood, suggesting a clinical use for this cytokine to enhance mobilization of hematopoietic progenitors from the bone marrow (Socinski et al. 1988). The ability of GM-CSF to mobilize EPC into peripheral blood was demonstrated with the use of a murine model of corneal vasculogenesis and a rabbit model of hind limb ischemia; in both instances, treatment of the animals with GM-CSF augmented the mobilization of EPC in response to ischemia (Socinski et al. 1988, Takahashi et al. 1999). A subset of cytokines known as chemokines is of particular importance for the homing of bone marrow-derived EPC to the site of injury. For instance, interleukin 8 (IL8) can augment neovascularization of ischemic myocardial tissue (Chavakis 2006, Kocher et al. 2006). In addition, local production of cytokines such as tumor necrosis factor α and G-CSF in turn triggers the production of angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietins, and fibroblast growth factors, which further promote the mobilization and incorporation of EPC into new blood vessels (Goukassian et al. 2007, Hattori et al. 2001, 2002, Minamino et al. 2005, Rabbany et al. 2003). Distinct from environmental cues, EPCs can also secrete their own cytokines and growth factors or can express

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surface receptors that enable them to migrate, home, and differentiate into ECs. Stimulating signaling by the chemokine (C-X-C motif) receptor 4 (CXCR4) improves migrating and homing capabilities of EPC, thus, restoring functional impairment of EPC in patients with coronary artery disease and improving their neovascularization capacity (Walter et al. 2005). The c-kit receptor is also implicated in mobilization of bone marrow-derived stem cell to ischemic heart. Mutations in the ckit receptor interfered with this migration process and reduced tissue repair (Fazel et al. 2006). At the site of inflammation, the in vitro and in vivo interaction of c-kit and its membranebound ligand is required for the recruitment of EPC (Dentelli et al. 2007). The phosphoinositide 3-kinase (PI3) kinase/PKB (protein kinase B) pathway is the only pathway known to be implicated in EPC proliferation, differentiation, and enhanced vasculogenesis (Dentelli et al. 2007, Dimmeler et al. 2001, Dimmeler and Zeiher 2000). 

Modulation of Cytokine and Growth Factor Receptor Signaling by Protein Tyrosine Phosphatases

Protein tyrosine phosphatases (PTPs) modulate the activity of various signaling molecules through dephosphorylation of key tyrosine residues and, thereby, regulate crucial signaling pathways that control stem cell proliferation and differentiation. Among the large family of PTP, four play a major role in regulating signaling through the cytokine and c-kit pathways and, hence, are likely critical to stem cell development: protein tyrosine phosphatase 1B (PTP1B), its close homologue T cell protein tyrosine phosphatase (TC-PTP), and Scr homology phosphatase 1 (SHP-1) and 2. Although other PTPs are implicated in hematopoietic development and regulation of endothelial function, this review focuses only on nontransmembrane PTPs that participate in growth factor and cytokine signaling within the cytoplasm and nucleus. In spite of their extensive homology, PTP1B and TC-PTP differ in their cellular localization, function, and regulation. Each has specific substrates within the Janus kinase (JAK) family of signaling molecules: whereas PTP1B regulates JAK2 and tyrosine kinase 2 (TYK2), TC-

PTP modulates cytokine signaling via JAK1 and JAK3. Substrate specificity also varies for the downstream STAT molecules: STAT5 is a substrate for both PTP1B and TC-PTP, whereas STAT1 and STAT6 (Lu et al. 2007) are unique substrates for TC-PTP. Through dephosphorylation of these signaling molec u l e s , b o t h P T P 1B a n d T C - P T P function as negative regulators of cytokine signaling (reviewed in Bourdeau et al. 2005). Accordingly, loss of function of these PTP causes hyperactivation of multiple cytokine signaling pathways, resulting in abnormal hematopoietic and perhaps endothelial lineage development. Both PTPs are expressed in hematopoietic cells (Bourdeau et al. 2005). In TC-PTP-deficient (tc-ptp−/−) mice, abnormal development of several hematopoietic lineages (erythroid, lymphoid, and monocytic) was noted (YouTen et al. 1997). Impaired B-cell development results chiefly from a defect of the bone marrow stroma owing to abnormal secretion of interferon γ (Bourdeau et al. 2007); a cell-autonomous defect of lymphoid precursors plays a minor role. TC-PTP is also a critical regulator of mononuclear phagocyte development through modulation of CSF-1 signaling (Simoncic et al. 2006). In contrast, gene targeting of PTP1B in mice yields animals with predominantly metabolic defects. These mice display enhanced insulin, leptin, and growth hormone (GH) sensitivity, and are resistant to diet-induced diabetes and obesity (Elchebly et al. 1999). However, PTP1B has also been described as an important modulator of myeloid differentiation and macrophage activation in vivo (Heinonen et al. 2006), erythrocyte development through regulation of the erythropoietin (Epo) receptor (Cohen et al. 2004), and a role for PTP1B in B-cell development has recently been demonstrated with the study of tumorigenesis in ptp1b−/− mice (Dube et al. 2005). Similar to PTP1B and TC-PTP, SHP1 and 2 are also negative regulators of cytokine signaling through JAK and STAT molecules. JAK1, JAK2, JAK3, and STAT5 are substrates for SHP-1; and JAK2, STAT1, and STAT2 are substrates for SHP-2. SHP-1 diminishes the growth-promoting activity of CSF-1, Epo, and IL-3. SHP-2 has been shown to regulate signaling pathways for

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multiple growth factors, including stem cell factor (SCF), IL-3, macrophage colony-stimulating factor, GM-CSF, and Epo (reviewed in Salmond and Alexander 2006, Tsui et al. 2006). In addition, both SHP-1 and 2 can modulate signaling through the c-kit receptor and are involved in regulation of the PI3 kinase/ Akt pathway. SHP-1 acts downstream of the c-kit receptor and negatively regulates c-kit signaling in a cell-specific manner (Lorenz et al. 1996, Paulson et al. 1996). In contrast, when bound to the adaptor molecule Gab2, SHP-2 can activate mast cell proliferation (Yu et al. 2006). The importance of SHP-2 in maintaining stem cell homeostasis has been demonstrated in bone marrow isolated from mice bearing only one functional copy of the shp-2 gene (Chan et al. 2006). In competitive transplantation and serial retransplantation assays, bone marrowderived stem cells from these animals

demonstrated reduced potential for stem cell repopulation. Although homing of transplanted cells was preserved, their capacity for self-renewal was impaired (Chan et al. 2006). Although it may seem counterintuitive that decreased inhibition of signaling should result in decreased cell proliferation, the signaling abnormality in shp-2+/− stem cells was not characterized. Nevertheless, these observations indicate that the homeostatic activity of PTP consists in more than a simple off switch, but instead is part of a complex interplay of activating and inhibitory signals. 

Regulation of EPC Development by PTPs

With the combined knowledge of the factors that influence stem cell activity and the targets of PTP activity, it becomes possible to examine the role played by each phosphatase at various

Figure 2. Regulation of EPC development by PTPs.

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stages of stem cell development. Of particular interest to vascular medicine are the events that lead EPC from the bone marrow microenvironment into target organs where they may participate in vasculogenesis (Figure 2). Within the bone marrow, EPC may adopt one of two fates: self-renewal or differentiation. Both imply a capacity for proliferation. Insulin (Humpert et al. 2008) and Epo (Heeschen et al. 2003) are factors that promote mitogenesis. Signaling through the receptor for insulin-like growth factor 1 is inhibited by PTP1B, which dephosphorylates the receptor tyrosine kinase (Buckley et al. 2002). PTP1B is also a negative regulator of Epo signaling through dephosphorylation of the receptor (Cohen et al. 2004). Similarly, SHP-1 inhibits Epo signaling through direct binding of the receptor and dephosphorylation of JAK2 and STAT5 (Sharlow et al. 1997) (Figure 2). The process of stem cell differentiation into EPC and CEPC is regulated, among others, by platelet-derived growth factor (PDGF) and GH. Signaling by PDGF, in turn, is regulated by TC-PTP (Persson et al. 2004) and its homologue PTP1B (Haj et al. 2003). PTP1B also attenuates GH-mediated JAK2 and STAT signaling (Gu et al. 2003). Thus, the activity of factors that affect the fate of progenitors in the endothelial lineage is controlled by common PTP (Figure 2). Circulating EPC must exit the bone marrow and enter into the systemic circulation to reach target organs. Bone-resorbing osteoclasts are involved in mobilization of EPC from the bone marrow microenvironment to the circulation, both in homeostatic and stressinduced conditions (Kollet et al. 2006). Multiple factors have been identified, which promote the mobilization and migration of EPC: Epo (Heeschen et al. 2003), VEGF (Rabbany et al. 2003), GCSF (Nienaber et al. 2006), GM-CSF (Takahashi et al. 1999), GH (Thum et al. 2007), as well as signaling through the c-kit receptor (Dentelli et al. 2007, Fazel et al. 2008). Chemokines have also been shown to play a pivotal role in mobilizing EPC, particularly stromal cell-derived factor 1 and its receptor CXCR4 (Shepherd et al. 2006, Walter et al. 2005). Most of these are regulated by SHP-1 and SHP2, although PTP1B also participates in the regulation of Epo and GH signaling, as discussed previously. SHP-1 inhibits

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signaling by Epo (Sharlow et al. 1997) and c-kit (Lorenz et al. 1996, Paulson et al. 1996). It also attenuates the effects of VEGF by enhancing tumor necrosis factor α-mediated inhibition of VEGF signaling (Guo et al. 2000, Sugano et al. 2007) and regulates signaling by the GCSF receptor (Ward et al. 2000). SHP-2 decreases activation of the Ras/extracellularly regulated kinase (ERK) mitogenactivated protein kinase (MAPK) axis triggered by GM-CSF signaling (Chan et al. 2006). In contrast, recruitment of SHP-2 to the c-kit receptor is required for activation of the MAPK pathway, at least in mast cells (Yu et al. 2006). Similarly, SHP-1 and SHP-2 have opposite effects on signaling by CXCR4. Whereas SHP-1 inhibits this receptor (Kim et al. 1999), SHP-2 associates with CXCR4 and potentiates signaling by activating Fyn and Lyn tyrosine kinases, as well as the ubiquitin ligase Cbl (Chernock et al. 2001). The same PTPs that control emigration of EPC from the bone marrow are implicated in their egress from the bloodstream into solid tissues, because both processes share common stimuli, such as signaling through the c-kit receptor (Dentelli et al. 2007, Fazel et al. 2008), which is regulated by SHP-1 (Lorenz et al. 1996, Paulson et al. 1996) and SHP-2 (Yu et al. 2006) (Figure 2). Ultimately, the fate of EPCs is to participate in vasculogenesis, either directly by differentiating into ECs and incorporating into nascent vessel structures or indirectly through the secretion of cytokines and growth factors that enhance this process. Predictably, the same factors that promote stem cell differentiation into EPC in the bone marrow also promote EPC differentiation into functional ECs. Thus, insulin (Humpert et al. 2008), VEGF (Rabbany et al. 2003), PDGF (Li et al. 2003), and GH (Thum et al. 2007) have each been shown to promote the angiogenic potential of EPC. Accordingly, TC-PTP and PTP1B play a major regulatory role at this stage of EC development because they do during differentiation of bone marrow stem cells into EPC (Figure 2). 

Clinical Use of PTP Inhibitors

From the above discussion, it would appear that particular subsets of PTP are more involved at certain steps in stem

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cell development and less at others. Hence, despite the multiplicity of factors that regulate these developmental milestones, intracellular regulatory mechanisms integrate complex signals and, therefore, constitute attractive targets for pharmacologic manipulation of stem cell biology. Indeed, experimental evidence in animals indicates that inhibition of PTP activity can have profound effects on EC function and neovascularization. Inhibition of PTP1B activity with chemical inhibitors has been shown to restore endothelial function in a murine model of congestive heart failure (Vercauteren et al. 2006). After coronary artery ligation, mice develop congestive heart failure and EC dysfunction, characterized by impaired nitric oxide (NO) production, leading to loss of flowmediated dilatation. Inhibition of PTP1B enhances endothelial NO synthase and Akt phosphorylation and normalizes NO production in response to flow. An improvement in neovascularization after ischemic injury has also been observed after inhibition of SHP-1 in a rat model of hind limb ischemia (Sugano et al. 2007). Abrogating SHP-1 activity with small interfering RNA (siRNA) led to enhanced VEGF-mediated tyrosine phosphorylation of Flk-1, resulting in increased capillary density. In contrast, decreasing SHP-2 activity was shown to impair vessel growth in vivo with the use of a chick chorioallantoic membrane assay (Mannell et al. 2008). In this model, treatment with SHP-2 antisense oligodeoxynucleotides or a pharmacologic inhibitor resulted in decreased phosphorylation of Akt and increased apoptosis. Together, these experiments suggest a potential therapeutic use for PTP inhibitors to treat endothelial dysfunction and vascular disease. From a clinical perspective, the finding that different PTPs have opposite effects underscores the importance of devising inhibitors with specificity for a single PTP. Strategies to optimize the delivery and potentially increase the efficacy of PTP inhibitors include local administration (e.g., by injection at the desired site) and ex vivo treatment of target cells. An instance where such an approach might be valuable is in clinical trials with the use of EPC for the treatment of acute myocardial infarction (reviewed in Boyle et al. 2006, Cleland et al. 2006). In all such trials, the protocol involves harvest-

ing either whole bone marrow or peripheral blood progenitor cells from patients having recently experienced an acute myocardial infarction for reinjection at a later time point, typically 4 to 5 days after the event. This provides a window of time during which progenitor cells might be treated with the pharmacologic inhibitor of choice to enhance their capacity for vascular repair. Other clinical applications for PTP inhibitors can be envisaged wherever enhancing neovascularization might be beneficial. The clinical application of PTP inhibitors for the treatment of vascular disease clearly is feasible. Clinical trials will be required to confirm the safety and efficacy of this potential novel therapy. 

Acknowledgments

This work has been supported by operating grants from the Canadian Institutes of Health Research (Ottawa, ON, Canada) (PPP 82568; MOP-62887) and the National Cancer Institute of Canada (Toronto, ON, Canada) (015200). M.L.T. is a recipient of the Jeanne and Jean-Louis Lévesque Chair in Cancer Research. A.B. is supported by the US Lymphoma Foundation (New York, NY). References Akashi K: 2005. Lineage promiscuity and plasticity in hematopoietic development. Ann N Y Acad Sci 1044:125–131. Asahara T, Masuda H, Takahashi T, et al.: 1999. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85: 221–228. Bourdeau A, Dube N & Tremblay ML: 2005. Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Curr Opin Cell Biol 17: 203–209. Bourdeau A, Dube N, Heinonen KM, et al.: 2007. TC-PTP-deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-gamma. Blood 109:4220–4228. Boyle AJ, Schulman SP, Hare JM & Oettgen P: 2006. Is stem cell therapy ready for patients? Stem cell therapy for cardiac repair. Ready for the Next Step. Circulation 114:339–352. Buckley DA, Cheng A, Kiely PA, et al.: 2002. Regulation of insulin-like growth factor type I (IGF-I) receptor kinase activity by protein tyrosine phosphatase 1B (PTP-1B) and enhanced IGF-I-mediated suppression of apoptosis and motility in PTP-1B-

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Novel Biomarkers for Predicting Preeclampsia David M. Carty, Christian Delles, and Anna F. Dominiczak⁎

Preeclampsia is a major cause of maternal morbidity and mortality worldwide. Despite decades of research into the condition, the ability of clinicians to predict preeclampsia prior to the onset of symptoms has not improved significantly. In this review, we will examine the pathophysiology underlying preeclampsia and will look at potential biomarkers for early prediction and diagnosis. In addition, we will explore potential future areas of research into the condition. (Trends Cardiovasc Med 2008;18:186–194) n 2008, Elsevier Inc. 

Introduction

Preeclampsia is a multisystem disorder of pregnancy, which complicates 3%-5% of pregnancies in the western world. It is

David M. Carty, Christian Delles, and Anna F. Dominiczak are at the BHF Glasgow Cardiovascular Research Centre, University of Glasgow, G12 8TA Glasgow, United Kingdom. ⁎ Address correspondence to: Prof. Anna F. Dominiczak, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, G12 8TA Glasgow, United Kingdom. Tel.: (+44) 141 330 5420; fax: (+44) 141 330 6997; e-mail: [email protected]. © 2008 Elsevier Inc. All rights reserved. 1050-1738/08/$-see front matter

a major cause of maternal morbidity and mortality worldwide. The cardinal clinical features of the condition are hypertension and proteinuria occurring after 20 weeks gestation in women who were not previously known to be hypertensive. Other signs and symptoms include edema and headache, and in severe cases, the condition is associated with seizures (eclampsia), liver, and kidney dysfunction as well as clotting abnormalities, Adult Respiratory Distress Syndrome and fetal growth restriction (FGR) (Davison et al. 2004). The cause of preeclampsia remains unknown, and the only known cure is delivery of the fetus and placenta.

TCM Vol. 18, No. 5, 2008