A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus.
A key mechanism underlying physiological angiogenesis of the human endometrium is its ability to regenerate the vascular capillary network and to perform vascular remodeling (i.e., development of spiral arteries). Vascular endothelial growth factor (VEGF) is associated with angiogenesis and capillary permeability in this tissue. VEGF is expressed as several spliced variants, its main human isoforms contain 121 and 165 aa; 17beta-estradiol (E(2)) increases endometrial VEGF, possibly in all isoforms. Here we show that progesterone (P) selectively increases the expression of the VEGF(189) (V(189)) isoform in the human uterus. V(189) is identified in the conditioned medium of stromal cells treated with E(2) + P; its presence in this in vitro model of decidual stromal cells is detected after 6-8 days, using ELISA, and after 8-10 days, using Western blot analysis with different antibodies, including one specific for V(189). The secretion pattern of V(189) parallels that of the decidual protein IGFBP-1. V(189) is secreted as a native isoform, as compared with the migration of recombinant V(189) by SDS/PAGE. In situ hybridization and immunocytochemistry(,) performed on the same biopsies, suggest that decidual cells express V(189) during the mid-late secretory phase of the menstrual cycle and early gestation. Finally, using an in vivo permeability assay, we show that native V(189) increases capillary permeability. These observations demonstrate that P regulates V(189) expression in decidual cells, which could have important implications for understanding uterine vascular remodeling and implantation, and may be relevant in a range of disease states such as edema and irregular bleeding.
Ancelin
Magali
M
Institut National de la Santé et de la Recherche Médicale (INSERM) U553, "Hémostase, Endothélium et Angiogénèse," Hôpital Saint Louis/Bât INSERM, 1 Avenue C. Vellefaux, 75010 Paris, France.
Buteau-Lozano
Hélène
H
Meduri
Geri
G
Osborne-Pellegrin
Mary
M
Sordello
Sylvie
S
Plouët
Jean
J
Perrot-Applanat
Martine
M
D002199:Capillary Permeability; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000737:chemistry* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008222:Lymphokines / Q000737:chemistry* / Q000378:metabolism; D008597:Menstrual Cycle; D018919:Neovascularization, Physiologic; D011233:Precipitin Tests; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014599:Uterus / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D020033:Protein Isoforms; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011374:Progesterone; D004958:Estradiol