The HGR motif is the antiangiogenic determinant of vasoinhibin : implications for a therapeutic orally active oligopeptide

The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.“Consejo Nacional de Ciencia y Tecnología” (CONACYT) and UNAM grant.http://link.springer.com/journal/10456ImmunologyNeurolog

Integrative genomic analysis reveals a conserved role for prolactin signalling in the regulation of adrenal function

International audienceNo abstract availabl

Protection of Glial Müller Cells by Dexamethasone in a Mouse Model of Surgically Induced Blood-Retinal Barrier Breakdown

PURPOSE. Breakdown of the inner blood-retinal barrier (iBRB) occurs in many retinal disorders and may cause retinal edema often responsible for vision loss. Dexamethasone is used in clinical practice to restore iBRB. The aim of this study was to characterize the impact of a surgically induced iBRB breakdown on retinal homeostatic changes due to dystrophin Dp71, aquaporin-4 (AQP4), and Kir4.1 alterations in Müller glial cells (MGC) in a mouse model. The protective effect of dexamethasone was assessed in this model. Moreover, retinal explants were used to control MGC exposure to a hypoosmotic solution containing barium. METHODS. Partial lens surgery was performed in C57BL6/J mice. Dystrophin Dp71, AQP4, and Kir4.1 expression was analyzed by quantitative RT-PCR, Western blot, and immunohistochemistry. Twenty-four hours after surgery, mice received a single intravitreal injection of dexamethasone or of vehicle. RESULTS. After partial lens surgery, iBRB permeability increased while Dp71 and AQP4 were downregulated and Kir4.1 was delocalized. These effects were partially prevented by dexamethasone injection. In the retinal explant model, MGC were swollen and Dp71, AQP4, and Kir4.1 were downregulated after exposure to a hypoosmotic solution containing barium, but not in the presence of dexamethasone. Heat shock factor protein 1 (HSF1) was overexpressed in dexamethasone-treated retinas. CONCLUSIONS. Partial lens surgery induces iBRB breakdown and molecular changes in MGC, including a downregulation of Dp71 and AQP4 and the delocalization of Kir4.1. Dexamethasone seems to protect retina from these molecular changes by upregulating HSF1