From Bench to Bedside: Translating the Prolactin/Vasoinhibin Axis

Abstract

The prolactin/vasoinhibin axis defines an endocrine system, in which prolactin (PRL) and vasoinhibins regulate blood vessel growth and function, the secretion of other hormones, inflammatory and immune processes, coagulation, and behavior. The core element of the PRL/vasoinhibin axis is the generation of vasoinhibins, which consists in the proteolytic cleavage of their precursor molecule PRL. Vasoinhibins can interact with multiple different partners to mediate their effects in various tissues and anatomical compartments, indicating their pleiotropic nature. Based on accumulating knowledge about the PRL/vasoinhibin axis, two clinical trials were initiated, in which vasoinhibin levels are the target of therapeutic interventions. One trial investigates the effect of levosulpiride, a selective dopamine D2-receptor antagonist, on retinal alterations in patients with diabetic macular edema and retinopathy. The rationale of this trial is that the levosulpiride-induced hyperprolactinemia resulting in increased retinal vasoinhibins could lead to beneficiary outcomes in terms of a vasoinhibin-mediated antagonization of diabetes-induced retinal alterations. Another trial investigated the effect of bromocriptine, a dopamine D2-receptor agonist, for the treatment of peripartum cardiomyopathy. The rationale of treatment with bromocriptine is the inhibition of vasoinhibin generation by substrate depletion to prevent detrimental effects on the myocardial microvascularization. The trial demonstrated that bromocriptine treatment was associated with a high rate of left ventricular recovery and low morbidity and mortality. Therapeutic interventions into the PRL/vasoinhibin axis bear the risk of side effects in the areas of blood coagulation, blood pressure, and alterations of the mental state.

Prolactin: The Third Hormone in Breast Cancer

“…Furthermore, PRL can modulate angiogenesis. As an intact protein, it can promote vascularization ( 88 , 89 ); in contrast, its proteolytic products (vasoinhibins) impede this process ( 90 ). These activities have suggested roles in normal mammary function as well as breast cancer ( 91 ).…”

Development of Vasoinhibin-Specific Monoclonal Antibodies

“…The fact that circulating vasoinhibin levels are unknown and cannot be monitored is a significant barrier for the translation of the role of the prolactin/vasoinhibin axis in health and disease. It is also a safety concern in interventional trials in which the generation of vasoinhibin is pharmacologically interfered with, for example in the trials evaluating blocking vasoinhibin generation in patients with peripartum cardiomyopathy or stimulating it in patients with diabetic retinopathy ( 15 ).…”

Vasoinhibin comprises a three-helix bundle and its antiangiogenic domain is located within the first 79 residues

“…This axis regulates the angiogenesis required for the growth and function of reproductive and non-reproductive organs and contributes to the pathogenesis of angiogenesis-related retinal and cardiac diseases and diseases occurring during and after pregnancy 10 , 26 , 27 . Moreover, the conversion of PRL to vasoinhibin is the basis of two clinical trials in which vasoinhibin is the target of therapeutic interventions 28 . However, the molecular transition of PRL to vasoinhibin is poorly understood and there is no information regarding the solution structure of vasoinhibin.…”