Hypoxia and hypoxia inducible factor-1α are required for normal endometrial repair during menstruation

Abstract

Heavy menstrual bleeding (HMB) is common and debilitating, and often requires surgery due to hormonal side effects from medical therapies. Here we show that transient, physiological hypoxia occurs in the menstrual endometrium to stabilise hypoxia inducible factor 1 (HIF-1) and drive repair of the denuded surface. We report that women with HMB have decreased endometrial HIF-1α during menstruation and prolonged menstrual bleeding. In a mouse model of simulated menses, physiological endometrial hypoxia occurs during bleeding. Maintenance of mice under hyperoxia during menses decreases HIF-1α induction and delays endometrial repair. The same effects are observed upon genetic or pharmacological reduction of endometrial HIF-1α. Conversely, artificial induction of hypoxia by pharmacological stabilisation of HIF-1α rescues the delayed endometrial repair in hypoxia-deficient mice. These data reveal a role for HIF-1 in the endometrium and suggest its pharmacological stabilisation during menses offers an effective, non-hormonal treatment for women with HMB.

Long non‐coding RNA MALAT1 mediates hypoxia‐induced pro‐survival autophagy of endometrial stromal cells in endometriosis

“…Sampson's transplantation and implantation theory, which is the most widely accepted assumption, indicates that endometriosis occurs due to the reflux of endometrial debris by retrograde menstruation . However, because retrograde menstruation occurs in most women but only 5%‐10% develop endometriosis, other factors such as peritoneal hypoxia microenvironment must contribute to the development of this disease . According to Sampson's theory, when shed endometrial cells or debris retrogrades to the peritoneal cavity, the first stress faced is the local altered hypoxic microenvironment.…”

“…The key factor mediating cellular hypoxia response is the hypoxia‐inducible factor‐1 (HIF‐1), which is a heterodimeric transcription factor composed of an O 2 ‐sensitive α‐subunit and a constitutively expressed β‐subunit . In women susceptible to endometriosis, it is probable that retrograde menstruation of endometrial cells or debris that attach to the peritoneal wall may be exposed to hypoxic‐ischaemic peritoneal microenvironment . Previous studies reported that hypoxia may play a role in the survival and angiogenesis of retrograde endometrial cells in implanted ectopic endometriotic lesions .…”

Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils

“…To directly assess the role of hypoxia in PMN-tumor cell interactions, we housed PRPL mice in a 60% O 2 environmental chamber. This high level of respiratory O 2 exposure is thought to increase oxygen delivery to tissues by increasing the partial pressure of O 2 dissolved in arterial blood (36) and was previously shown to be able to improve the oxygenation of the non-tumor-bearing mouse uterus (37). We chose to house the mice in the chamber starting on postnatal day 18 (P18), because this time point corresponded to when the tumors first started accumulating PMNs and showing signs of hypoxia (5), and to sacrifice them 10 days later on P28, because P28 was the primary terminal end point we employed in our previous study (5).…”

The Link Between Human Menstruation and Placental Delivery: A Novel Evolutionary Interpretation

“…This event, in conjunction with tissue dissolution, attends both menstruation and placental detachment, and, together with enhanced cellular degradation of the uterine cellular matrix, results in endometrial shedding and placental detachment . In menstruation, immediately following placental delivery, there is a rapid regeneration of the endometrial tissue, perhaps facilitated directly or indirectly by progesterone withdrawal . Placental detachment differs from menstruation in that it is preceded by intense myometrial contractions (i.e., labor), which induce birth (Figure ), and during which uterine blood flow to the placenta has to be maintained.…”