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产生深远的公共利益。骨形态发生蛋白 (BMP) 正在成为脉管系统的重要调节因子，对于动静脉畸形 (AVM) 等疾病非常重要。先前的研究表明，BMP-4 和基质 Gla 蛋白 (MGP)（一种 BMP 拮抗剂）可调节血管生成中必需的激活素样激酶受体 1 (ALK1) 的表达。 ALK1 的配体 BMP-9 刺激后可调节内皮细胞增殖和成熟。我们的初步数据表明，ALK1 信号传导有助于调节 Notch 信号传导，而 Notch 信号传导与脑 AVM 相关。数据进一步表明，MGP 缺乏会增强 BMP 和 Notch 信号传导，导致脑 AVM 的形成和血管内皮细胞 (EC) 的异常分化。 MGP 缺乏还会导致内皮细胞中干细胞标记物的表达，并破坏正常的管腔形成。总之，结果表明 MGP 在血管发育过程中 BMP 和 Notch 信号传导之间的串扰中发挥着关键作用。我们假设 MGP 有助于维持 BMP 和 Notch 信号传导之间的平衡，从而指导正常血管化，并且 BMP 信号传导增强会增强 Notch 信号传导并导致 AVM。我们进一步假设，Notch 信号传导的限制会减少 MGP 缺乏时的脑 AVM，部分是通过限制血管细胞中的干细胞特征和异常的管腔形成。具体目标 1 将测试 MGP 对体外和体内 EC 分化过程中 BMP 信号和 Notch 信号之间相互作用的影响。具体目标 2 将确定 Notch 信号传导的减少是否可以补偿 MGP 缺陷，并通过将 MGP 缺陷小鼠与 Notch 配体 Jag1 或 Jag2 缺陷小鼠交配来限制脑 AVM。我们预测，由于 MGP 缺乏，Notch 配体水平较低将限制脑 AVM。具体目标 3 将使用体外 MGP 耗竭和体内谱系追踪来确定 MGP 在调节内皮干细胞特征和血管腔形成中的作用，作为 AVM 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.