Progesterone modulates integrin {alpha}2 (ITGA2) and {alpha}11 (ITGA11) in the pregnant cervix.
OBJECTIVE
Fibrillar collagen in the cervical extracellular matrix (ECM) is the predominant component providing mechanical support. Cellular integrins contribute to structural integrity by cross-linking ECM components. We investigated the expression of collagen-binding integrins in the normal rat gestation and after treatment with mifepristone to determine whether integrin modulation is involved in changes in tissue resistance.


METHODS
Cervical tissue was harvested from nonpregnant and timed pregnant Sprague-Dawley rats. Normal gestational expression was evaluated in nonpregnant and timed pregnant tissue on days 12, 16, 18, 20, 21 and 22. Progesterone inhibition was induced with 3 mg mifepristone administered on day 15. Primary rat cervical stromal (RCS) cell cultures were generated from nonpregnant rats using tissue explants. The effects of progesterone environment on RCS cells were evaluated in the presence and absence of various inhibitors. Protein expression and signaling pathways were evaluated by Western blot.


RESULTS
Integrin α2 (ITGA2) expression increased over gestation, peaking at the end of gestation (analysis of variance [ANOVA] P < .01). Integrin α11 (ITGA11) expression increased through mid-gestation, peaking on day 18 and decreasing through day 22 (ANOVA P < .001). Progesterone increased the expression of ITGA11 and phosphorylated focal adhesion kinase ([pFAK] P < .002). Mifepristone blocked these effects in vitro. Mifepristone increased ITGA2 and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) in vivo and in vitro. Mifepristone-induced upregulation of ITGA2 was abrogated by inhibition of ERK1/2.


CONCLUSIONS
Progesterone/progesterone withdrawal is involved in regulating the expression of collagen-binding integrins. These changes differ among the collagen-binding integrins. Mitogen-activated protein kinase (MAPK) signaling is involved in regulating some of these integrins.
Department of Obstetrics and Gynecology, Section of Maternal Fetal Medicine, The Warren Alpert Medical School of Brown University, Women & Infants' Hospital of Rhode Island, Providence, RI 02905, USA.
Huiling
H
Ji
Vit
V
Long
Victoria
V
Briody
Edward K
EK
Chien
D000818:Animals; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D039001:Integrin alpha Chains / Q000378:metabolism*; D039421:Integrin alpha2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D015735:Mifepristone / Q000494:pharmacology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects / Q000502:physiology*; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017154:Stromal Cells / Q000378:metabolism
D006727:Hormone Antagonists; C558437:ITGA11 protein, rat; D039001:Integrin alpha Chains; D039421:Integrin alpha2; D015735:Mifepristone; D011374:Progesterone; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases