title: Inflammatory mediators and endometrial function--focus on the perivascular cell.
abstract: Human endometrium has a unique vascular architecture that allows menstruation, the shedding of a well-vascularised tissue layer, with limited bleeding. Blood loss is controlled at least in part by constriction of the perivascular cells, myofibroblasts that surround the spiral arterioles and have contractile activity. These perivascular cells, which are coupled to endothelial cells by processes, are responsive to changes in progesterone levels and express chemokines, cytokines and prostaglandins (PG) crucial to the control of leukocyte entry into endometrium. In this location the chemokine interleukin-8 (IL-8) and prostaglandin E (PGE) will have synergistic effects on leukocyte entry. CD40 is also expressed on the perivascular cells. Activation of CD40 by CD40 ligand is known to increase COX-2 and IL-8 expression in endometrial fibroblasts. The likely source of CD40 ligand in the uterus is platelets. Thus ingress of platelets will up-regulate NFkappaB by activating CD40 and increase agents such as PGE which will stimulate further the ingress of platelets. There is thus the possibility of a spiralling inflammatory response. This response however, is normally modulated by progesterone raising the threshold of the NFkappaB pathway and in the presence of high progesterone levels activation of CD40 will be ineffective. When progesterone falls at the end of the ovarian cycle and the restrictions on activation are lost, the perivascular cells will respond, initiating leukocyte entry, vasoconstriction-vasodilatation cycles with associated hypoxia and consequent sloughing off of the endometrium. The perivascular cell in endometrium is pivotal in both menstruation and early pregnancy and we need to understand this cell better to devise more effective medical treatment for menstrual dysfunction.
authors.affiliation: Human Reproductive Sciences Unit, Medical Research Council, Centre for Reproductive Biology, University of Edinburgh, UK. r.kelly@ed-rbu.mrc.ac.uk
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Kelly
authors.forename: Anne E
authors.initials: AE
authors.lastname: King
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
mesh_terms: D001160:Arterioles / Q000166:cytology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002465:Cell Movement; D016207:Cytokines / Q000502:physiology; D004717:Endometrium / Q000098:blood supply / Q000166:cytology* / Q000276:immunology / Q000502:physiology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007962:Leukocytes / Q000502:physiology; D008598:Menstruation / Q000502:physiology; D008954:Models, Biological; D011374:Progesterone / Q000502:physiology
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D023201:CD40 Ligand; D011374:Progesterone