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EDITORIAL |
MRC Human Reproductive Sciences, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
Correspondence should be addressed to H N Jabbour; Email: h.jabbour{at}hrsu.mrc.ac.uk
The vascular system develops through two distinct pathways commonly referred to as vasculogenesis and angiogenesis. The former involves formation of vascular networks from endothelial progenitor cells, which can originate from bone marrow and peripheral blood (Kassmeyer et al. 2009). In contrast, angiogenesis involves the growth of new blood vessels from pre-existing ones. Vascular growth is a common feature of wound healing, inflammatory diseases and in the transition of tumours into a malignant state. Blood vessel growth is tightly regulated in the healthy adult; most organs do not need to form new blood vessels; however, one site where new blood vessel formation is normal in adulthood is the female reproductive tract.
In non-pregnant and pregnant females, growth of new blood vessels is crucial for proper functioning of the ovary, endometrium and the placenta. Many disorders and diseases of the female reproductive tract (such as polycystic ovarian syndrome, unscheduled or excessive endometrial bleeding, endometriosis, pre-eclampsia and cancers) involve alterations in the growth and functioning of the vasculature (Smith 2001, Giudice & Kao 2004, Critchley et al. 2006, Jabbour et al. 2006, Fraser & Duncan 2008). Understanding the molecular processes that govern growth and function of blood vessels in physiological settings may help us to develop new therapies for those female reproductive tract pathologies that are promoted either by growth of new blood vessels or by altered functioning of established ones. There is much to be learnt from the female reproductive tract in the way it initiates and controls blood vessel growth cyclically every menstrual cycle and in pregnancy. Such knowledge may inform us about how to halt vessel growth in pathological contexts within the reproductive tract and elsewhere in the body. It may also inform us about how to initiate and regulate vascular growth and function during wound healing and following ischaemic injury such as myocardial infarction.
Vasculogenesis is crucial for the establishment of the vascular bed of the placenta and is evident from days 18–20 post conception. In this Focus Issue, Burton et al. (2009) summarise the current knowledge about the molecular regulation of vasculogenesis and angiogenesis and their contribution to vascular growth and function in the human placenta. Although the role of vasculogenesis in blood vessel formation in the adult ovary and uterus is not as clearly defined, transgenic mouse models suggest that circulating endothelial progenitor cells do contribute to the formation of new vessels in the corpus luteum and endometrium (Asahara et al. 1999). Evidence also exists for contribution of endothelial progenitor cells to vascular growth in the human endometrium. Endothelial cells with XY genotype have been detected in the endometrium of women who received an allogeneic bone marrow transplant from a male (Mints et al. 2008). However, it is well accepted that angiogenesis predominantly contributes to the intense cyclical growth of the vasculature in the ovary and endometrium. Future work using novel live bioimaging technologies and fluorescent labelling methods may inform us about the contribution of bone marrow cells and resident blood vessels to in vivo vascularisation of the female reproductive tract and its diseases such as endometriosis and cancer. Another component of the vasculature that has been neglected until recently is the lymphatic system. Their distinction from blood vessels has been enhanced with the discovery of molecules that are specifically expressed on lymph vessels (Bruyere & Noe 2009). This has facilitated the generation of reagents that can be used experimentally to distinguish between blood and lymph vessels. Much of what we know about local lymphatic systems comes from cancer biology as lymph vessels play a crucial role in metastatic spread of tumour cells (Bruyere & Noe 2009). However, more knowledge about their genesis and functional regulation in the reproductive tract is warranted considering their important role in regulating interstitial fluid content and immune cell trafficking (Red-Horse 2008).
The isolation of vascular endothelial growth factor (VEGF) by Leung et al. (1989) has dramatically improved our knowledge about the molecular regulation of angiogenesis. We now know that the VEGF system is very complex with the existence of numerous isoforms, receptors and co-receptors (Gabhann & Popel 2008). Girling & Rogers (2009) provide a scholarly account of the importance and diversity of the VEGF molecules and their signalling partners to regulate both blood and lymphatic vessels. Robinson et al. (2009) discuss the importance of the VEGF system and the balance with other pro- and anti-angiogenic factors on vessel function in the ovary. They also present parallels for regulation of vascular function between different species highlighting the conservation of function of many of these systems. Mural cells, such as pericytes and vascular smooth muscle cells, provide important structural properties to the vasculature, which can regulate blood flow and vascular permeability. They also play a crucial role in vascular remodelling during implantation and placental development. Perturbations in these remodelling events may contribute to several common gestational pathologies, which highlights the need for more research to better understand the cell–cell communication that occurs between mural cells and the surrounding stroma and endothelial cells.
As reviewed by Jabbour et al. (2009), it is well accepted now that many physiological reproductive events such as ovulation, menstruation, implantation and onset of labour display classic signs of inflammation. The onset and maintenance of many reproductive disorders are the result of exacerbated inflammatory or deficient resolution pathways. These events are orchestrated by a dialogue between cells of the immune system and the vasculature. Neutrophils, macrophages and uterine natural killer cells are recognised for the pro-inflammatory, angiogenic and tissue remodelling roles that they play in reproductive events. However, emerging evidence highlights the important role for immune cells such as neutrophils in resolution of inflammation and tissue repair, which is fundamental to the resumption of proper reproductive function (Kaitu'u-Lino et al. 2007). A better understanding of these multiple roles, and the pervading hormonal environment that regulates immune cell function in the reproductive tract, will better inform us about the evolution of reproductive pathologies that are inflammatory in nature.
This Focus Issue of Reproduction provides several reviews that address our current knowledge about the regulation of vascular function in female reproduction in humans and farm animals. They also highlight emerging areas of research that will improve our knowledge about this complex area of biology.
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Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M & Isner J 1999 Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularisation. Circulation Research 85 221–228.
Bruyere F & Noe A 2009 Lymphangiogenesis: in vitro and in vivo models. FASEB Journal[in press]. DOI: 10.1096/fj.09-132852.
Burton GJ, Charnock-Jones DS & Jauniaux E 2009 Regulation of vascular growth and function in human placenta. Reproduction 138 895–902.
Critchley HOD, Kelly RW, Baird DT & Brenner RM 2006 Regulation of human endometrial function: mechanisms relevant to uterine bleeding. Reproductive Biology and Endocrinology 4 S5.[CrossRef]
Fraser H & Duncan C 2008 Regulation and manipulation of angiogenesis in the ovary and endometrium. Reproduction, Fertility, and Development 21 377–392.[CrossRef]
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Girling JE & Rogers PAW 2009 Regulation of endometrial vascular remodeling: role of the vascular endothelial growth factor family and the angiopoietin–tie signalling system. Reproduction 138 883–893.
Giudice LC & Kao LC 2004 Endometriosis. Lancet 364 1789–1799.[CrossRef][Web of Science][Medline]
Jabbour HN, Kelly RW, Fraser HM & Critchley HOD 2006 Endocrine regulation of menstruation. Endocrine Reviews 27 17–46.
Jabbour HN, Sales KJ, Catalano RD & Norman JE 2009 Inflammatory pathways in female reproductive health and disease. Reproduction 138 903–919.
Kaitu'u-Lino TJ, Morison NB & Salamonsen LA 2007 Neutrophil depletion retards endometrial repair in a mouse model. Cell and Tissue Research 328 197–206.[CrossRef][Web of Science][Medline]
Kassmeyer S, Plendl J, Custodis P & Bahramsoltani M 2009 New insights in vascular development: vasculogenesis and endothelial progenitor cells. Anatomia, Histologia, Embryologia 38 1–11.[CrossRef][Web of Science]
Leung DW, Cachianes G, Kuang WJ, Goeddel DV & Ferrara N 1989 Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246 1306–1309.
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.
Red-Horse K 2008 Lymphatic vessels in the uterine wall. Placenta 29 S55–S59.[CrossRef][Web of Science][Medline]
Robinson RS, Woad KJ, Hammond AJ, Laird M, Hunter MG & Mann GE 2009 Angiogenesis and vascular function in the ovary. Reproduction 138 869–881.
Smith SK 2001 Regulation of angiogenesis in the endometrium. Trends in Endocrinology and Metabolism 12 147–151.[CrossRef][Web of Science][Medline]
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