Impact of inter-network remodeling on reproduction – Repro-Net

We will use a combination of mouse genetic models and viral transduction, with ex vivo and in vivo (GRINlens) imaging of both anaesthetised and conscious mice to study the function of the GVU and consequences of its dysregulation for LH output. Pituitary blood flow, changes in vascularity and its regulation by pericytes will be correlated with the response of gonadotrophs to the secretagogue GnRH at both metestrus and proestrus and the release of LH, measured with ultrasensitive ELISA.
The consequences of altering pericyte activity for regulation of gonadotroph function and hormone output of the gland, as well as the signaling pathways underlying gonadotroph-pericyte cross talk will be determined, providing targets for its modification in therapy for reproductive disorders. As the crosstalk between the prolactin and gonadotroph axis have previously been identified as having an important role in normal reproductive function we will also focus on the relationship of lactotrophs with the GVU, in particular with respect to the prolactin metabolite vasoinhibin, which has been identified as modifying vascular function in other systems. The selection of therapeutic targets to modulate gonadotroph response to GnRH will be aided by modeling, which will identify the key components of GVU function for optimal and regulated LH release.

Based on the complementary extertise of our consortium, 3 hypotheses are currently addressed as follows:
1. That the remodeling of the GVU leads to modification of their dynamic interaction and contributes to an enhanced hormone output during the LH surge.
2. That these GVU elements are altered in animal models reproducing hormone dysregulation in PCOS.
Promissing anatomical fonctional data were already acquired with regards the first question and the animal model for PCOS will be soon studied in all labs of the consortium Repro-Net.
A first article has already been published (Nat Rev Endoc) which coined the concept of the functional relationship between pituitary endocrine cells and vascular system.

We will use a clinically relevant model of dysregulation of LH secretion, polycystic ovarian syndrome (PCOS), to both determine the components of the GVU which may be altered in this condition and test the efficacy of our model. The potential of therapeutic targets modifying signalling within the GVU, prioritized through our modeling studies, will be tested in the PCOS model, with implications for the treatment of this disorder as well as others of the reproductive system in humans.

Le Tissier P, Campos P, Lafont C, Romanò N, Hodson DJ, Mollard P. An updated view of hypothalamic-vascular-pituitary unit function and plasticity. Nat Rev Endocrinol. 2017 May;13(5):257-267.

7 oral communications and posters.

The hypothalamic-pituitary-gonadal (HPG) axis controls sexual maturation and reproductive function. A key component of the function of this axis is the pulsatile output of LH from the pituitary gland, with a surge of secretion required for ovulation. Despite the high prevalence of infertility and a wealth of scientific studies, the mechanisms regulating the pattern of basal and pre-ovulatory LH secretion are still poorly understood. Our preliminary data identifies a Gonadotroph-Vasculature Unit (GVU) in which crosstalk between the network of LH-secreting pituitary gonadotrophs and the vasculature (pericytes and fenestrated endothelial cells) regulates the dynamics of delivery of regulatory factors from the hypothalamus, the response of the gonadotroph cells and intravasation of the secreted LH into the bloodstream. Crosstalk with other cell networks, in particular the closely apposed lactotroph network, may be prerequisites for regulation of LH release into the bloodstream since prolactin and LH release are coordinated at proestrus.
We now plan to study this axis using the complementary skills and animal models of our French-Mexican consortium to address this GVU working hypothesis. We will use a combination of mouse genetic models and viral transduction, with ex vivo and in vivo (GRINlens) imaging of both anaesthetised and conscious mice to study the function of the GVU and consequences of its dysregulation for LH output. Pituitary blood flow, changes in vascularity and its regulation by pericytes will be correlated with the response of gonadotrophs to the secretagogue GnRH at both metestrus and proestrus and the release of LH, measured with ultrasensitive ELISA.
The consequences of altering pericyte activity for regulation of gonadotroph function and hormone output of the gland, as well as the signaling pathways underlying gonadotroph-pericyte cross talk will be determined, providing targets for its modification in therapy for reproductive disorders. As the crosstalk between the prolactin and gonadotroph axis have previously been identified as having an important role in normal reproductive function we will also focus on the relationship of lactotrophs with the GVU, in particular with respect to the prolactin metabolite vasoinhibin, which has been identified as modifying vascular function in other systems. The selection of therapeutic targets to modulate gonadotroph response to GnRH will be aided by modeling, which will identify the key components of GVU function for optimal and regulated LH release.
Finally we will use a clinically relevant model of dysregulation of LH secretion, polycystic ovarian syndrome (PCOS), to both determine the components of the GVU which may be altered in this condition and test the efficacy of our model. The potential of therapeutic targets modifying signalling within the GVU, prioritized through our modeling studies, will be tested in the PCOS model, with implications for the treatment of this disorder as well as others of the reproductive system in humans.