Prolactin stimulates the vascularisation of the retina in newborn mice under hyperoxia conditions

Vázquez-Membrillo, Miguel; Siqueiros‐Márquez, Lourdes; Núñez, Francisco Freinet; Díaz‐Lezama, Nundehui; Adán‐Castro, Elva; Ramírez‐Hernández, Gabriela; Adán, Norma; Macotela, Yazmín; Escalera, Gonzálo Martínez de la; Clapp, Carmen

doi:10.1111/jne.12858

Cited by 6 publications

(7 citation statements)

References 36 publications

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“…Retinal angiogenesis was determined in CD1 neonate mice as reported [ 40 ]. Vi45–51 (300 μg kg −1 ) or vehicle were administered intraperitoneally every 12 h from postnatal day (P) 3 to 8.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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“…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 ).…”

Section: Prl Actions In Development Of Breast Cancermentioning

confidence: 99%

Prolactin: The Third Hormone in Breast Cancer

Schuler

O’Leary

2022

Front. Endocrinol.

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Prolactin coordinates with the ovarian steroids to orchestrate mammary development and lactation, culminating in nourishment and an increasingly appreciated array of other benefits for neonates. Its central activities in mammary epithelial growth and differentiation suggest that it plays a role(s) in breast cancer, but it has been challenging to identify its contributions, essential for incorporation into prevention and treatment approaches. Large prospective epidemiologic studies have linked higher prolactin exposure to increased risk, particularly for ER+ breast cancer in postmenopausal women. However, it has been more difficult to determine its actions and clinical consequences in established tumors. Here we review experimental data implicating multiple mechanisms by which prolactin may increase the risk of breast cancer. We then consider the evidence for role(s) of prolactin and its downstream signaling cascades in disease progression and treatment responses, and discuss how new approaches are beginning to illuminate the biology behind the seemingly conflicting epidemiologic and experimental studies of prolactin actions across diverse breast cancers.

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“…[5][6][7] The generation of vasoinhibin depends on PRL levels and the activity of PRL-cleaving proteases regulated at the hypothalamus, the pituitary, and the target tissue levels defining the PRL/vasoinhibin axis. 8 This axis helps maintain corneal avascularity, 9 restricts retinal vasculature, 10 and is disrupted in retinopathy of prematurity 11,12 and DR. 13 Furthermore, the overexpression of ocular vasoinhibin inhibits ischaemia-induced retinal angiogenesis 14 and prevents and reverses diabetes-induced retinal hypervasopermeability in rodents. [15][16][17] These observations have led to the hypothesis that medications causing hyperprolactinaemia, resulting in higher levels of vasoinhibin, could be beneficial in DME and DR. 18 One such medication is levosulpiride, a prokinetic frequently used to treat diabetic gastroparesis, 19 that is highly effective for inducing hyperprolactinaemia as it blocks dopamine D2 receptors in the anterior pituitary gland.…”

Section: Prolactin Acquires Antivasopermeability and Antiangiogenicmentioning

confidence: 99%

“…The generation of vasoinhibin depends on PRL levels and the activity of PRL‐cleaving proteases regulated at the hypothalamus, the pituitary, and the target tissue levels defining the PRL/vasoinhibin axis 8 9 restricts retinal vasculature, 10 and is disrupted in retinopathy of prematurity 11,12 and DR 13 . Furthermore, the overexpression of ocular vasoinhibin inhibits ischaemia‐induced retinal angiogenesis 14 and prevents and reverses diabetes‐induced retinal hypervasopermeability in rodents 15–17 …”

Section: Introductionmentioning

confidence: 99%

Sulpiride‐induced hyperprolactinaemia increases retinal vasoinhibin and protects against diabetic retinopathy in rats

Adán‐Castro

Siqueiros‐Márquez

Ramírez‐Hernández

et al. 2022

J Neuroendocrinology

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Excessive vasopermeability and angiogenesis compromise vision in diabetic macular oedema (DME) and diabetic retinopathy (DR). Vasoinhibin is a fragment of the hormone prolactin (PRL) that inhibits diabetes-induced retinal hypervasopermeability and ischaemia-induced retinal angiogenesis in rodents. Hyperprolactinaemia generated by the dopamine D2 receptor antagonist, levosulpiride, is associated with higher levels of vasoinhibin in the vitreous of patients with DR, implying a beneficial outcome due to vasoinhibin-mediated inhibition of retinal vascular alterations. Here, we tested whether hyperprolactinaemia induced by racemic sulpiride increases intraocular vasoinhibin levels and inhibits retinal hypervasopermeability in diabetic rats. Diabetes was generated with streptozotocin and, 4 weeks later, rats were treated for 2 weeks with sulpiride or osmotic minipumps delivering PRL. ELISA, Western blot, and Evans blue assay were used to evaluate serum PRL, retinal vasoinhibin, and retinal vasopermeability, respectively. Hyperprolactinaemia in response to sulpiride or exogenous PRL was associated with increased levels of vasoinhibin in the retina and reduced retinal hypervasopermeability. Furthermore, sulpiride decreased retinal haemorrhages in response to the intravitreal administration of vascular endothelial growth factor (VEGF). Neither sulpiride nor exogenous PRL modified blood glucose levels or bodyweight. We conclude that sulpiride-induced hyperprolactinaemia inhibits the diabetes-and VEGF-mediated increase in retinal vasopermeability by promoting the intraocular conversion of endogenous PRL to vasoinhibin. These findings support the therapeutic potential of sulpiride and its levorotatory enantiomer, levosulpiride, against DME and DR.

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Prolactin stimulates the vascularisation of the retina in newborn mice under hyperoxia conditions

Cited by 6 publications

References 36 publications

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

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

Prolactin: The Third Hormone in Breast Cancer

Sulpiride‐induced hyperprolactinaemia increases retinal vasoinhibin and protects against diabetic retinopathy in rats

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