Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2).
The menstrual cycle is a complex interaction of sex steroids, prostanoids, and cytokines that lead to coordinated tissue degradation, regeneration and repair. The transcription factor hypoxia-inducible factor (HIF-1) plays critical roles in cellular responses to hypoxia, the generation of an inflammatory response and vasculogenesis through transcriptional activation of angiogenic genes. We hypothesize that HIF-1 is expressed in human endometrium and that locally synthesized prostaglandins (PGE2 and PGF(2alpha)) regulate HIF-1 activity. Here we demonstrate that PGE2 up-regulates HIF-1alpha mRNA and protein via the E-series prostanoid receptor 2 (EP2), and this up-regulation is dependent on epidermal growth factor receptor kinase activity. We show the tight temporal-spatial confinement of HIF-1alpha protein expression in endometrium across the cycle. HIF-1alpha is expressed exclusively during the secretory and menstrual phases. Protein expression is maximal at progesterone withdrawal during the late secretory and menstrual phase. HIF-1alpha protein colocalizes with prostaglandin EP2 receptor in glandular cells. In contrast, HIF-1beta/aryl receptor nuclear translocator 1 expression occurs throughout the cycle but is maximal in glandular cells during the proliferative phase. This provides evidence for a role for HIF-1 in the menstrual cycle and demonstrates that HIF-1 activation in human endometrium may occur via a PGE2-regulated pathway and provides a coordinated pathway from progesterone withdrawal through to angiogenic gene expression via HIF-1.
Critchley
Hilary O D
HO
University of Edinburgh, Centre for Reproductive Biology, The Queen's Medical Research Building, Scotland, UK. hilary.critchley@ed.ac.uk
Osei
Julia
J
Henderson
Teresa A
TA
Boswell
Lyndsey
L
Sales
Kurt J
KJ
Jabbour
Henry N
HN
Hirani
Nik
N
D004717:Endometrium / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008597:Menstrual Cycle / Q000378:metabolism; D011458:Prostaglandins E / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D018709:Statistics, Nonparametric; D015854:Up-Regulation
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C545644:PTGER2 protein, human; D011458:Prostaglandins E; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D066246:ErbB Receptors