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.

催乳素激素在经过蛋白水解裂解为血管抑制素后获得抗血管生成和抗血管通透性特性，血管抑制素是一种由 123 个或更多氨基酸组成的内源性催乳素片段，可抑制多种促血管生成因子的作用。临床前和临床证据支持血管抑制素对血管生成相关疾病的治疗潜力，包括糖尿病视网膜病变、围产期心肌病、类风湿性关节炎和癌症。然而，血管抑制素在临床上的使用因其生产困难而受到限制。在这里，我们通过证明仅由三个残基 (His46-Gly47-Arg48) (HGR) 组成的短线性基序是血管抑制素的功能决定因素，消除了使用血管抑制素作为治疗剂的障碍。 HGR基序在整个进化过程中是保守的，其突变导致血管抑制素功能丧失，含有该序列的寡肽抑制血管生成和血管通透性，其效力与整个血管抑制素相同。此外，口服含有HGR的优化循环逆向血管抑制素七肽可抑制小鼠黑色素瘤肿瘤的生长和血管形成，并表现出与目前临床上用作抗癌药物的其他抗血管生成分子相同或更高的抗血管生成效力。最后，通过揭示催乳素中 HGR 基序的隐藏机制，我们预计血管抑制素特异性抗体的开发将解决为诊断和干预目的测量内源性血管抑制素水平的持续挑战，设计用于管理血管生成不足的血管抑制素拮抗剂，以及含有 HGR 的推定治疗蛋白的鉴定。