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具有深远的公共利益。骨形态发生蛋白（BMP）正在成为血管系统的重要调节因子，在动静脉畸形（AVM）等疾病中非常重要。以前的研究表明，BMP-4和基质玻璃蛋白（MGP），BMP拮抗剂，调节激活素样激酶受体1（ALK 1）的表达，在血管生成中必不可少。ALK 1通过其配体BMP-9的刺激，然后调节内皮细胞增殖和成熟。我们的初步数据显示，ALK 1信号传导有助于调节Notch信号传导，Notch信号传导与脑AVM相关。数据进一步显示，MGP缺乏增强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缺乏也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，从而指导正常血管形成，并且升高的BMP信号增强Notch信号并导致AVM。我们进一步假设，限制Notch信号传导将减少MGP缺乏的脑AVM，部分原因是限制了血管细胞中的干细胞特征和异常管腔形成。具体目标1将测试MGP在体外和体内EC分化期间对BMP信号传导和Notch信号传导之间的相互作用的影响。具体目标2将通过使MGP缺陷小鼠与Notch配体Jag 1或Jag 2缺陷小鼠交配来确定Notch信号传导的减少是否补偿MGP缺陷并限制脑AVM。我们预测，较低水平的Notch配体将限制脑AVM由于MGP缺乏。具体目标3将使用体外MGP耗竭和体内谱系追踪确定MGP在调节内皮干细胞特征和血管腔形成（作为AVM形成的一部分）中的作用。如果成功，所获得的信息可能转化为使用BMP和Notch抑制剂治疗脑AVM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.