From the Department of Immunology, Genetics, and Pathology, Uppsala University, Sweden (S.I.C., P.U.M., E.D.); FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); and Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
Circ Res. 2017 Sep 29;121(8):981-999. doi: 10.1161/CIRCRESAHA.117.309930.
Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-β/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-β/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-β/BMP receptor complex and the second to increased signaling sensitivity to TGF-β/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.
正确的血管树组织需要几种信号通路的平衡活动，这些信号通路调节管状形成和血管分支、延伸和修剪。当这种平衡被打破时，血管可能会畸形和脆弱，并可能失去动静脉分化。在这篇综述中，我们集中讨论转化生长因子 (TGF)-β/骨形态发生蛋白 (BMP) 途径，这是血管发育中最重要和最复杂的信号系统之一。这些途径的失活会导致胚胎中血管组织的改变。此外，许多血管畸形与 TGF-β/BMP 信号的失调有关。在这里，我们专注于两种由 TGF-β/BMP 信号失调引起的最受研究的血管畸形：遗传性出血性毛细血管扩张症 (HHT) 和脑动静脉畸形 (CCM)。前者与 TGF-β/BMP 受体复合物的功能丧失突变有关，后者与 TGF-β/BMP 信号敏感性增加有关。在这篇综述中，我们讨论了迄今为止针对这些血管畸形确定的潜在治疗靶点，以及它们在血管发育和稳定性的一般机制中的基础。
