BMP and Notch Crosstalk in Cerebral Arteriovenous Malformations

描述(由申请人提供)：血管疾病的治疗进展可能会对公众产生深远的影响。骨形态发生蛋白(BMPs)是血管系统的重要调节因子，在动静脉畸形(Avms)等疾病中发挥重要作用。以前的研究表明，BMP-4和BMP拮抗剂基质GLA蛋白(MGP)调节激活素样激酶受体1(ALK1)的表达，而ALK1是血管生成中必不可少的。ALK1的配体BMP-9刺激ALK1，然后调节内皮细胞的增殖和成熟。我们的初步数据显示，ALK1信号在调节Notch信号方面发挥了重要作用，而Notch信号与脑Avms有关。数据进一步表明，MGP缺乏同时增强了BMP和Notch信号，导致脑动静脉畸形的形成和血管内皮细胞的异常分化。MGP缺乏还会导致内皮细胞中干细胞标志物的表达，并扰乱正常管腔的形成。综上所述，这些结果表明MGP在血管发育过程中BMP和Notch信号之间的串扰中起着关键作用。我们假设MGP有助于维持BMP和Notch信号之间的平衡，Notch信号引导正常的血管形成，BMP信号升高增强Notch信号并导致动静脉动静脉畸形。我们进一步假设，限制Notch信号将减少MGP缺乏症患者的脑动静脉畸形，部分原因是限制了血管细胞中的干细胞特性和异常管腔形成。目的1研究MGP在体内外对EC分化过程中BMP信号和Notch信号相互作用的影响。具体目标2将通过用Notch配体Jag1或Jag2缺乏的小鼠饲养MGP缺陷小鼠来确定Notch信号的减少是否补偿了MGP缺乏并限制了大脑Avm。我们预测，由于MGP缺乏，较低水平的Notch配体将限制脑动静脉畸形。具体目标3将通过体外MGP耗竭和体内谱系追踪，确定MGP在调节内皮干细胞特性和血管腔形成中的作用，作为动静脉畸形形成的一部分。如果成功，获得的信息可能会转化为使用BMP和Notch抑制剂治疗脑动静脉畸形的策略。

DESCRIPTION (provided by applicant): Therapeutic advances in vascular disease may have far-reaching public benefits. Bone morphogenetic proteins (BMPs) are emerging as essential regulators of the vasculature, important in disorders such as arteriovenous malformations (AVMs). Previous studies have shown that BMP-4 and Matrix Gla Protein (MGP), a BMP antagonist, regulate the expression of the activin-like kinase receptor 1 (ALK1), essential in angiogenesis. Stimulation of ALK1 by its ligand BMP-9 then regulates endothelial proliferation and maturation. Our preliminary data show that ALK1 signaling is instrumental in regulating Notch signaling, which has been associated with cerebral AVMs. The data further show that MGP deficiency enhances both BMP and Notch signaling resulting in the formation of cerebral AVMs and abnormal differentiation of vascular endothelial cells (ECs). MGP deficiency also causes the expression of stem cell markers in endothelial cells and disrupts normal lumen formation. Together, the results suggest that MGP plays a critical role in the crosstalk between BMP and Notch signaling during vascular development. We hypothesize that MGP helps maintain the balance between BMP and Notch signaling, which directs normal vascularization, and that elevated BMP signaling enhances Notch signaling and leads to AVMs. We further hypothesize that a limitation of Notch signaling would reduce cerebral AVMs in MGP deficiency, in part by limiting stem cell characteristics in vascular cells and abnormal lumen formation. Specific Aim 1 will test the effects of MGP on the interactions between BMP signaling and Notch signaling during EC differentiation in vitro and in vivo. Specific Aim 2 will determine if a reducton in Notch signaling compensates for MGP deficiency and limits cerebral AVMs by breeding the MGP deficient mice with mice deficient in Notch ligands Jag1 or Jag2. We predict that lower levels of Notch ligands will limit the cerebral AVMs due to MGP deficiency. Specific Aim 3 will determine the role of MGP in regulating endothelial stem cell characteristics and vascular lumen formation as part of the formation of AVMs using MGP depletion in vitro and lineage tracing in vivo. If successful, the obtained information may translate into strategies for using BMP and Notch inhibitors in the treatment of cerebral AVMs.