Molecular Mechanisms of Matrix GLA Protein (MGP)

描述(由申请人提供)：心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)和糖尿病血管病变等疾病中具有重要作用。我们的数据显示，内皮BMP4活性导致两种BMP抑制剂的顺序诱导，基质GLA蛋白(MGP)和Crossveinless-2(CV2)。MGP抑制BMP4，当缺乏时，允许在内皮、血管钙化和动静脉畸形中出现干细胞标记物。CV2缺乏会导致内皮细胞异常增厚，而干细胞标记物不会增加。我们的数据提出了一个两步模型，其中MGP调节血管前体细胞的增殖和干细胞特性，而CV2调节承诺的内皮细胞的增殖和成熟。在这个两步模型中，我们假设BMP4和MGP调节血管祖细胞池的大小，而BMP9和CV2调节承诺的EC池的大小。因此，BMP4活性增强或MGP减少将允许多能前体细胞成骨，从而导致血管钙化。MGP和CV2可能在糖尿病微血管异常和动静脉动静脉畸形的调节中发挥重要作用。我们假设，通过操纵MGP和CV2，我们将能够抑制这些抑制物发挥作用的血管异常。具体目标1将在体外和体内测试EC谱系分化的两步模型的有效性。该模型预测，提高MGP水平将限制 血管紧张素转换酶2缺乏引起的内皮细胞过度生长。具体目标2将确定MGP和CV2在遗传性出血性毛细血管扩张症(HHT)小鼠模型中对动静脉动静脉畸形形成的贡献。我们的模型预测，通过MGP或CV2增加BMP抑制将限制HHT的迹象。特异靶3将确定BMP抑制调控糖尿病血管病变的机制。MGP和CV2被预测为阶段特异性的BMP抑制剂，不充分的BMP抑制将允许在糖尿病Ins2Akita/+小鼠模型中的主动脉和微血管系统中出现血管病变。如果成功，获得的信息可能会转化为使用BMP抑制剂治疗血管疾病的策略。

DESCRIPTION (provided by applicant): Therapeutic advances in cardiovascular 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) and diabetic vasculopathy. Our data show that endothelial BMP4 activity causes a sequential induction of two BMP inhibitors, Matrix Gla Protein (MGP) and Crossveinless-2 (Cv2). MGP inhibits BMP4, and when deficient, allows the emergence of stem cell markers in the endothelium, vascular calcification, and AVMs. Deficiency of Cv2 leads to an abnormal and thickened endothelium, without the increase in stem cell markers. Our data suggest a 2-step model where MGP regulates proliferation and stem cell characteristics in vascular progenitor cells, and Cv2 regulates proliferation and maturation of committed ECs. In this 2-step model, we hypothesize that BMP4 and MGP regulate the size of the vascular progenitor pool, whereas BMP9 and Cv2 regulate the size of the committed EC pool. Thus, enhanced BMP4 activity or decreased MGP would allow for osteogenesis in the multipotent progenitor cells leading to vascular calcification. Both MGP and Cv2 may play important roles in the regulation of diabetic microvascular abnormalities and AVMs. We hypothesize that by manipulating MGP and Cv2, we will be able to inhibit the vascular abnormalities in which these inhibitors play a role. Specific Aim 1 will test the validity of a 2-step model of EC lineage differentiation in vitro and in vivo. The model predicts that elevating the level of MGP will limit excessive endothelial growth resulting from Cv2 deficiency. Specific Aim 2 will determine the contribution of MGP and Cv2 to the formation of AVMs in a mouse model of hereditary hemorrhagic telangiectasia (HHT). Our model predicts that increasing BMP inhibition through MGP or Cv2 will limit the signs of HHT. Specific Aim 3 will determine the mechanism by which BMP inhibition could regulate diabetic vasculopathy. MGP and Cv2 are predicted to be stage-specific BMP inhibitors, and inadequate BMP inhibition would allow for vascular pathology in the aorta and the microvasculature as modeled by the diabetic Ins2Akita/+ mouse. If successful, the obtained information may translate into strategies for using BMP inhibitors in treating vascular disease.