Cignarella Andrea, Fadini Gian Paolo, Bolego Chiara, Trevisi Lucia, Boscaro Carlotta, Sanga Viola, Seccia Teresa Maria, Rosato Antonio, Rossi Gian Paolo, Barton Matthias
Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.
Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
Cardiovasc Res. 2022 Mar 16;118(4):988-1003. doi: 10.1093/cvr/cvab096.
Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration, and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signalling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects. Clinically, the most common side effects of VEGF signalling pathway inhibition include an increase in arterial pressure, left ventricular dysfunction facilitating the development of heart failure, thromboembolic events including pulmonary embolism and stroke, and myocardial infarction. Sex steroids, such as androgens, progestins, and oestrogens and their receptors (ERα, ERβ, GPER; PR-A, PR-B; AR) have been identified as important modifiers of angiogenesis, and sex differences have been reported for anti-angiogenic drugs. This review article discusses the current challenges clinicians are facing with regard to angiogenesis inhibitor therapy, including the need to consider sex differences affecting clinical efficacy and safety. We also propose areas for future research taking into account the role of sex hormone receptors and sex chromosomes. Development of new sex-specific drugs with improved target- and cell-type selectivity likely will open the way to personalized medicine in men and women requiring anti-angiogenic therapy to reduce adverse effects and to improve therapeutic efficacy.
血管活性分子，如血管内皮生长因子（VEGF）和内皮素，具有类似细胞因子的活性，可调节内皮细胞（EC）的生长、迁移和炎症。一些内皮介质及其受体是目前已获批的血管生成抑制剂的作用靶点，这些药物要么是针对VEGF的单克隆抗体，要么是血管受体蛋白激酶和信号通路的抑制剂。对内皮细胞保护功能的药理干扰会导致一系列类似的不良反应。临床上，抑制VEGF信号通路最常见的副作用包括动脉血压升高、促进心力衰竭发展的左心室功能障碍、包括肺栓塞和中风在内的血栓栓塞事件以及心肌梗死。雄激素、孕激素和雌激素等性类固醇及其受体（ERα、ERβ、GPER；PR-A、PR-B；AR）已被确定为血管生成的重要调节因子，并且已有关于抗血管生成药物存在性别差异的报道。这篇综述文章讨论了临床医生在血管生成抑制剂治疗方面目前面临的挑战，包括需要考虑影响临床疗效和安全性的性别差异。我们还提出了未来研究的领域，同时考虑到性激素受体和性染色体的作用。开发具有更高靶点和细胞类型选择性的新型性别特异性药物，可能会为需要抗血管生成治疗的男性和女性开辟个性化医疗的道路，以减少不良反应并提高治疗效果。
