期刊
ENDOCRINOLOGY
卷 147, 期 2, 页码 744-753出版社
ENDOCRINE SOC
DOI: 10.1210/en.2005-1153
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资金
- Medical Research Council [MC_U127684438, U.1276.00.004.00002.01/2(61014)] Funding Source: Medline
- MRC [MC_U127684438] Funding Source: UKRI
- Medical Research Council [G9900991B, MC_U127684438] Funding Source: researchfish
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(2 alpha)) regulate HIF-1 activity. Here we demonstrate that PGE2 up-regulates HIF-1 alpha 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-1 alpha protein expression in endometrium across the cycle. HIF-1 alpha is expressed exclusively during the secretory and menstrual phases. Protein expression is maximal at progesterone withdrawal during the late secretory and menstrual phase. HIF-1 alpha protein colocalizes with prostaglandin EP2 receptor in glandular cells. In contrast, HIF-1 beta/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.
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