Abstract
A dysregulation of the generation of vasoinhibin hormones by proteolytic cleavage of prolactin (PRL) has been brought into context with diabetic retinopathy, retinopathy of prematurity, preeclampsia, pregnancy-induced hypertension, and peripartum cardiomyopathy. Factors governing vasoinhibin generation are incompletely characterized, and the composition of vasoinhibin isoforms in human tissues or compartments, such as the circulation, is unknown. The aim of this study was to determine the possible contribution of PRL point mutations to the generation of vasoinhibins as well as to project their role in vasoinhibin-related diseases. Prolactin sequences, point mutations, and substrate specificity information about the PRL cleaving enzymes cathepsin D, matrix metalloproteinases 8 and 13, and bone-morphogenetic protein 1 were retrieved from public databases. The consequences of point mutations in regard to their possible effect on vasoinhibin levels were projected on the basis of a score indicating the suitability of a particular sequence for enzymatic cleavage that result in vasoinhibin generation. The relative abundance and type of vasoinhibin isoforms were estimated by comparing the relative cleavage efficiency of vasoinhibin-generating enzymes. Six point mutations leading to amino acid substitutions in vasoinhibin-generating cleavage sites were found and projected to either facilitate or inhibit vasoinhibin generation. Four mutations affecting vasoinhibin generation in cancer tissues were found. The most likely composition of the relative abundance of vasoinhibin isoforms is projected to be 15 > 17.2 > 16.8 > 17.7 > 18 kDa vasoinhibin. Prolactin point mutations are likely to influence vasoinhibin levels by affecting the proteolysis efficiency of vasoinhibin-generating enzymes and should be monitored in patients with vasoinhibin-related diseases. Attempts to characterize vasoinhibin-related diseases should include the 15, 17.2, 16.8, 17.7, and 18 kDa vasoinhibin isoforms.
Highlights
The regulation of blood vessel growth, pressure, permeability, and dilation is essential for all vertebrate species and is in part executed by hormones such as vasoinhibins [1,2,3]
Data concerning the suitability of cleavage site amino acid sequence for proteolytic cleavage by cathepsin D, matrix metalloproteinases (MMP), and bone-morphogenetic protein 1 (BMP-1) with subsequent generation of vasoinhibins were retrieved from databases, and a projection for single amino acid substitutions was performed
Six point mutations leading to a single amino acid substitution in cleavage sites affecting four vasoinhibin isoforms were found http://www.ensembl.org. 2 http://cancer.sanger.ac.uk/cosmic. 3 http://merops.sanger.ac.uk
Summary
The regulation of blood vessel growth, pressure, permeability, and dilation is essential for all vertebrate species and is in part executed by hormones such as vasoinhibins [1,2,3]. Apart from their vascular effects, vasoinhibins exert non-vascular actions, which include the stimulation of vasopressin release [4], proinflammatory actions [5] thrombolytic effects [6], and the stimulation of anxiety- and depression-related behaviors [7]. Vasoinhibins are generated by the proteolytic cleavage of their precursor molecule, the pituitary hormone prolactin (PRL). The aim of this study was to determine the possible contribution of PRL point mutations to the generation of vasoinhibins as well as to project their role in vasoinhibin-related diseases
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