A comparative phylogenetic analysis of prolactin cleavage sites for the generation of vasoinhibin in vertebrates

Leuchs, Andreas; Davies, Nils; Friedrich, Chr.; Trier, Sabrina; Clapp, Carmen; Bertsch, Thomas; Triebel, Jakob

doi:10.1016/j.ygcen.2022.114011

Cited by 3 publications

(3 citation statements)

References 32 publications

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“…This hormonal axis was described as the PRL/vasoinhibin axis of which the vasculature is a major target tissue (53,67). The cleavage sites in PRL through which vasoinhibin is generated are conserved in vertebrates (47, 67, 73) and high affinity cleavages sites evolved, most likely as a gain of function under positive selection, as a unique feature of higher primates (74). The cleavage of PRL to generate vasoinhibin occurs in the wider context of a hormone-metabolism junction, through which specifically cleaved hormones regulate essential functions to maintain homeostasis at the organismal, tissue, or organ levels (75,76).…”

Section: The Prl/vasoinhibin Axis Controls Ocular Angiogenesis and Va...mentioning

confidence: 99%

Prolactin and vasoinhibin are endogenous players in diabetic retinopathy revisited

Triebel

Bertsch²,

Clapp³

2022

Front. Endocrinol.

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Diabetic retinopathy (DR) and diabetic macular edema (DME) are major causes for visual loss in adults. Nearly half of the world’s population with diabetes has some degree of DR, and DME is a major cause of visual impairment in these patients. Severe vision loss occurs because of tractional retinal detachment due to retinal neovascularization, but the most common cause of moderate vision loss occurs in DME where excessive vascular permeability leads to the exudation and accumulation of extracellular fluid and proteins in the macula. Metabolic control stands as an effective mean for controlling retinal vascular alterations in some but not all patients with diabetes, and the search of other modifiable factors affecting the risk for diabetic microvascular complications is warranted. Prolactin (PRL) and its proteolytic fragment, vasoinhibin, have emerged as endogenous regulators of retinal blood vessels. PRL acquires antiangiogenic and anti-vasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, which helps restrict the vascularization of ocular organs and, upon disruption, promotes retinal vascular alterations characteristic of DR and DME. Evidence is linking PRL (and other pituitary hormones) and vasoinhibin to DR and recent preclinical and clinical evidence supports their translation into novel therapeutic approaches.

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Section: The Prl/vasoinhibin Axis Controls Ocular Angiogenesis and Va...mentioning

confidence: 99%

Prolactin and vasoinhibin are endogenous players in diabetic retinopathy revisited

Triebel

Bertsch²,

Clapp³

2022

Front. Endocrinol.

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“…For example, the HGR motif determining the bioactive site of vasoinhibin is conserved in mammals, birds, reptiles, amphibians, and fish [21]. In addition, the cleavage site responsible for the generation of a 15-kDa vasoinhibin isoform evolved in higher primates and has remained conserved [23]. Cleavage sites are usually defined as eight residues relevant for the recognition of the substrate, the formation of the transition state, and the subsequent disruption of the peptide bond between the residues.…”

Section: Active Protein Hormone Fragments: An Accident Of Birth?mentioning

confidence: 99%

New horizons in specific hormone proteolysis

Triebel

Robles

Zamora

et al. 2022

Trends in Endocrinology & Metabolism

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“…It is also generated in peripheral tissues ( 15 ). A high affinity cleavage site in PRL for the generation of vasoinhibin, which emerged in Simians and is conserved in higher primates, appears as a gain-of-function event under positive selection ( 16 ). Vasoinhibin is present in both, males and females.…”

Section: Introductionmentioning

confidence: 99%

Immunometric and functional measurement of endogenous vasoinhibin in human sera

Zamora,

Harris,

Davies

et al. 2024

Front. Endocrinol.

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IntroductionCirculating levels of the antiangiogenic protein vasoinhibin, a fragment of prolactin, are of interest in vasoproliferative retinopathies, preeclampsia, and peripartum cardiomyopathy; however, it is difficult to determine the circulating levels of vasoinhibin due to the lack of quantitative assays. MethodsThis study used human serum samples to assess the concentration and bioactivity of vasoinhibin using a novel enzyme-linked immunosorbent assay (ELISA) for human vasoinhibin, which employs an anti-vasoinhibin monoclonal antibody, a human umbilical vein endothelial cell (HUVEC) proliferation assay, and a chick chorioallantoic membrane (CAM) angiogenesis assay. ResultsSerum samples from 17 pregnant women without (one group) and with preeclampsia and pregnancy induced hypertension (another group) demonstrated endogenous vasoinhibin concentrations in the range of 5–340 ng/ml. Immunoactive vasoinhibin levels were significantly higher in preeclampsia serum compared to healthy pregnancy serum (mean 63.09 ± 22.15 SD vs. 19.67 ± 13.34 ng/ml, p = 0.0003), as was the bioactive vasoinhibin level as determined by the HUVEC proliferation assay (56.12 ± 19.83 vs. 13.38 ± 4.88 ng/ml, p < 0.0001). There was a correlation between the concentration of vasoinhibin measured by ELISA and the HUVEC proliferation assay (Pearson r = 0.95, p < 0.0001). Healthy serum demonstrated a proangiogenic effect in the CAM assay (p < 0.05, compared to control), while serum from preeclamptic patients demonstrated an antiangiogenic effect (p < 0.05 vs. control), as did recombinant human vasoinhibin and a synthetic circular retro-inverse vasoinhibin analogue (CRIVi45-51). The antiangiogenic effects in the CAM assay and the inhibition of HUVEC proliferation were abolished by addition of the ELISA anti-vasoinhibin monoclonal antibody, but not by mouse IgG. DiscussionThese results demonstrate the first quantitation of endogenous vasoinhibin in human sera and the elevation of it levels and antiangiogenic activity in sera from women with preeclampsia. The development and implementation of a quantitative assay for vasoinhibin overcomes a long-standing barrier and suggests the thorough clinical verification of vasoinhibin as a relevant biomarker.

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A comparative phylogenetic analysis of prolactin cleavage sites for the generation of vasoinhibin in vertebrates

Cited by 3 publications

References 32 publications

Prolactin and vasoinhibin are endogenous players in diabetic retinopathy revisited

Prolactin and vasoinhibin are endogenous players in diabetic retinopathy revisited

New horizons in specific hormone proteolysis

Immunometric and functional measurement of endogenous vasoinhibin in human sera

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