Abstract
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.
Highlights
Abnormal angiogenesis underlies multiple diseases characterized by excessive or insufficient proliferation of blood vessels including cancer, vasoproliferative retinopathies, rheumatoid arthritis, diabetic ulcers, cardiovascular disease, and many others [1]
The HGR motif is the antiangiogenic determinant of vasoinhibin
Like vasoinhibin [13, 14], Vi45–51 did not affect basal endothelial cell (EC) proliferation (Fig. 1c), antagonized the EC proliferation induced by various proangiogenic factors (VEGF, basic fibroblast growth factor (bFGF), IL-1β, and bradykinin)
Summary
Abnormal angiogenesis underlies multiple diseases characterized by excessive or insufficient proliferation of blood vessels including cancer, vasoproliferative retinopathies, rheumatoid arthritis, diabetic ulcers, cardiovascular disease, and many others [1]. Several endogenous antiangiogenic proteins and protein fragments have been identified as potential therapeutic agents [8,9,10] with advantages of small size, lower immunogenicity, higher specificity, and lower risk of drug resistance [8, 11, 12]. Some of these proteins are difficult to produce and have poor clinical performance [10, 11]. Vasoinhibin is a proteolytically generated fragment of the hormone prolactin (PRL) that inhibits the proliferation, migration, survival, and permeability of endothelial cells [13, 14]. We reasoned that the identification of the functional domain of vasoinhibin could lead to vasoinhibin-mimetics as alternative therapeutic molecules
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