title: Progesterone enhances vascular endothelial cell migration via activation of focal adhesion kinase.
abstract: The mechanisms of progesterone on endothelial cell motility are poorly investigated. Previously we showed that progesterone stimulated endothelial cell migration via the activation of actin-binding protein moesin, leading to actin cytoskeleton remodelling and the formation of cell membrane structures required for cell movement. In this study, we investigated the effects of progesterone on the formation of focal adhesion complexes, which provide anchoring sites for cell movement. In cultured human umbilical endothelial cells, progesterone enhanced focal adhesion kinase (FAK) phosphorylation at Tyr(397)  in a dose- and time-dependent manner. Several signalling inhibitors interfered with progesterone-induced FAK activation, including progesterone receptor (PR) antagonist ORG 31710, specific c-Src kinase inhibitor PP2, phosphatidylinosital-3 kinase (PI3K) inhibitor wortmannin as well as ρ-associated kinase (ROCK-2) inhibitor Y27632. It suggested that PR, c-Src, PI3K and ROCK-2 are implicated in this action. In line with this, we found that progesterone rapidly promoted c-Src/PI3K/Akt activity, which activated the small GTPase RhoA/ρ-associated kinase (ROCK-2) complex, resulting in FAK phosphorylation. In the presence of progesterone, endothelial cells displayed enhanced horizontal migration, which was reversed by small interfering RNAs abrogating FAK expression. In conclusion, progesterone promotes endothelial cell movement via the rapid regulation of FAK. These findings provide new information on the biological actions of progesterone on human endothelial cells that are relevant for vascular function.
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Zheng
authors.forename: Jinghe
authors.initials: J
authors.lastname: Huang
authors.forename: Kewen
authors.initials: K
authors.lastname: Zhou
authors.forename: Qiuling
authors.initials: Q
authors.lastname: Xiang
authors.forename: Yaxing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Tan
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Fu
authors.forename: Tinghuai
authors.initials: T
authors.lastname: Wang
mesh_terms: D000577:Amides / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004963:Estrenes / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011374:Progesterone / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D000077191:Wortmannin; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: C412373:AG 1879; D000577:Amides; D000730:Androstadienes; D004963:Estrenes; D005663:Furans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; C076196:Org 31710; C108830:Y 27632; D011374:Progesterone; D058539:Phosphatidylinositol 3-Kinase; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D000077191:Wortmannin