Decidualized human endometrial stromal cells mediate hemostasis, angiogenesis, and abnormal uterine bleeding.
Factor VII binds trans-membrane tissue factor to initiate hemostasis by forming thrombin. Tissue factor expression is enhanced in decidualized human endometrial stromal cells during the luteal phase. Long-term progestin only contraceptives elicit: 1) abnormal uterine bleeding from fragile vessels at focal bleeding sites, 2) paradoxically high tissue factor expression at bleeding sites; 3) reduced endometrial blood flow promoting local hypoxia and enhancing reactive oxygen species levels; and 4) aberrant angiogenesis reflecting increased stromal cell-expressed vascular endothelial growth factor, decreased Angiopoietin-1 and increased endothelial cell-expressed Angiopoietin-2. Aberrantly high local vascular permeability enhances circulating factor VII to decidualized stromal cell-expressed tissue factor to generate excess thrombin. Hypoxia-thrombin interactions augment expression of vascular endothelial growth factor and interleukin-8 by stromal cells. Thrombin, vascular endothelial growth factor and interleukin-8 synergistically augment angiogenesis in a milieu of reactive oxygen species-induced endothelial cell activation. The resulting enhanced vessel fragility promotes abnormal uterine bleeding.
Lockwood
Charles J
CJ
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Krikun
Graciela
G
Hickey
Martha
M
Huang
S Joseph
SJ
Schatz
Frederick
F
D000818:Animals; D015687:Cell Hypoxia; D003271:Contraceptive Agents, Female / Q000009:adverse effects; D003656:Decidua / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D004717:Endometrium / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006487:Hemostasis; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011372:Progestins / Q000009:adverse effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D014592:Uterine Hemorrhage / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D003271:Contraceptive Agents, Female; D016209:Interleukin-8; D011372:Progestins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D013925:Thromboplastin; D013917:Thrombin