Regulator of Angiogenesis and Vascular Function: A 2019 Update of the Vasoinhibin Nomenclature

摘要

Proteolytic cleavage of prolactin (PRL), the human anterior pituitary hormone fundamental for lactation can generate vasoinhibin, a peptide-hormone with endocrine, paracrine, and autocrine effects not shared with its precursor. Vasoinhibin effects include the regulation of blood vessel growth, permeability, and dilation ( 1 , 2 ), and non-vascular effects such as stimulation of vasopressin release ( 3 ), thrombolytic actions ( 4 ), inhibition of neurite outgrowth ( 5 ), and the stimulation of anxiety- and depression-related behaviors ( 6 ). Vasoinhibin signals through a still-unidentified receptor on endothelial cells distinct from the PRL-receptor and interacts with multiple binding partners ( 4 , 7 , 8 ). The role of vasoinhibin in biology and disease is evolving and its understanding requires the revision of its nomenclature, which is the purpose of this commentary ( 9 ). The regulation of vasoinhibin generation occurs at the hypothalamo, the pituitary, and the target tissue levels and this organizational principle is described as the prolactin/vasoinhibin axis ( 10 ). A dysregulation of this axis is relevant in several diseases. Recent studies have focused on retinal disorders ( 11 , 12 ), joint diseases ( 13 ), and pregnancy associated syndromes, for example diabetic retinopathy ( 11 , 14 ), rheumatoid arthritis ( 13 ), peripartum-cardiomyopathy ( 15 ), and pre-eclampsia ( 16 , 17 ). Two clinical trials in which vasoinhibin levels are the target of pharmacological interventions were initiated, one for the treatment of diabetic retinopathy and diabetic macular edema, and another for the treatment of peripartum cardiomyopathy ( 18 , 19 ). The principles and rationales behind these clinical trials were recently reviewed ( 20 ). Landmark studies on the physiological and pathophysiological effects of vasoinhibin are presented in Table 1 . Table 1 Landmark original research articles and reviews highlighting physiology and pathophysiological effects of vasoinhibin. Brief description Year References ORIGINAL RESEARCH ARTICLES Model of the three-dimensional structure of vasoinhibin, and localization of its functional domain 2018 ( 21 ) Clinical trial protocol on diabetic retinopathy and diabetic macular edema, pharmacological intervention into regulation of PRL/vasoinhibin axis 2018 ( 19 ) Suppression of neurotrophic VEGF and NGF-induced effects 2017 ( 5 ) Findings of a clinical trial on peripartum cardiomyopathy, pharmacological intervention into PRL/vasoinhibin axis 2017 ( 18 ) Binding partners and profibrinolytic action 2014 ( 4 ) Role on mammary gland involution in mice 2014 ( 22 ) Effects on anxiety- and depression-like behaviors in rats 2014 ( 6 ) Vasoinhibin gene therapy against diabetic retinopathy protects against VEGF- and diabetes-induced retinal vasopermeability in rats 2011 ( 14 ) Hyperprolactinemia in rodents leads to vasoinhibin accumulation in the retina 2010 ( 11 ) Cathepsin D generates vasoinhibin in rat anterior pituitary PRL secretory granules 2009 ( 23 ) Inhibition of vasopermeability in diabetic retinopathy 2008 ( 24 ) Impairment of cardiac capillary proliferation and function in peripartum cardiomyopathy 2007 ( 15 ) Vasoinhibin gene therapy against tumor growth and metastasis 2007 ( 25 ) Effect on endothelial cell dysfunction and low birth weight in preeclampsia 2007 ( 17 ) Bone morphogenetic protein 1 generates vasoinhibin 2007 ( 26 ) Matrix metalloproteases generate vasoinhibin 2006 ( 27 ) Inhibition of angiogenesis and vasodilation in the rat retina by endogenous vasoinhibin 2005 ( 28 ) Stimulation of vasopressin release 2003 ( 3 ) Stimulation of ocular vascular regression in retinopathy of prematurity by endogenous vasoinhibin 2004 ( 29 ) Inhibition of retinal angiogenesis in oxygen-induced retinopathy in mice 2004 ( 30 ) Inhibition of tumor growth in human colon cancer cells transplanted into mice 2001 ( 31 ) Proinflammatory effects in pulmonary fibroblasts and alveolar type II cells 2000 ( 32 ) Vasoinhibin contains the N-terminal region of PRL 1999 ( 33 ) Opposite effects of PRL and vasoinhibin on angiogenesis 1999 ( 34 ) Inhibition of corneal angiogenesis by exogenous and endogenous vasoinhibin 1999 ( 35 ) Cathepsin D generates vasoinhibin 1993 ( 36 ) Inhibition of in vitro and in vivo angiogenesis 1993 ( 37 ) Specific vasoinhibin binding sites in endothelial cell membranes 1992 ( 7 ) Discovery of antiangiogenic properties 1991 ( 38 ) Detection of vasoinhibin in the human pituitary gland and plasma 1985 ( 39 ) Cleavage of PRL by target tissues 1983 ( 40 ) Discovery of vasoinhibin as a functional PRL fragment in rat pituitary tissue 1980 ( 41 , 42 ) REVIEW ARTICLES Translational research, focus on diabetic retinopathy and peripartum cardiomyopathy 2017 ( 20 ) Involvement of the PRL/vasoinhibin axis in rheumatoid arthritis 2016 ( 13 ) First description of the PRL/vasoinhibin endocrine axis 2015 ( 10 ) Pathophysiological role of vasoinhibin in peripartum cardiomyopathy 2014 ( 43 ) Ph