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）和糖尿病血管病变等疾病中发挥重要作用。我们的数据表明，内皮BMP 4活性导致两种BMP抑制剂，基质玻璃蛋白（MGP）和Crossveinless-2（Cv2）的顺序诱导。MGP抑制BMP 4，当缺乏时，允许内皮、血管钙化和AVM中出现干细胞标志物。Cv2的缺乏导致异常和增厚的内皮，而没有干细胞标志物的增加。我们的数据表明一个2步模型，其中MGP调节血管祖细胞的增殖和干细胞特性，Cv2调节定向EC的增殖和成熟。在这个两步模型中，我们假设BMP 4和MGP调节血管祖细胞池的大小，而BMP 9和Cv2调节定向EC池的大小。因此，增强的BMP 4活性或降低的MGP将允许多能祖细胞中的骨生成，导致血管钙化。MGP和Cv2可能在糖尿病微血管异常和AVM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剂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2步模型的有效性。该模型预测，提高MGP水平将限制 由Cv2缺陷引起的过度内皮生长。特定目标2将确定MGP和Cv2对遗传性出血性毛细血管扩张症（HHT）小鼠模型中AVM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。具体目标3将确定BMP抑制剂调节糖尿病血管病变的机制。MGP和Cv2被预测为阶段特异性BMP抑制剂，并且不充分的BMP抑制将允许如由糖尿病Ins2Akita/+小鼠建模的主动脉和微脉管系统中的血管病理。如果成功，所获得的信息可能转化为使用BMP抑制剂治疗血管疾病的策略。 公共卫生相关性：我们的研究与心脏和血管疾病的治疗有关，如糖尿病患者常见的动脉硬化和遗传性出血性毛细血管扩张症，这是一种遗传性疾病。我们的研究集中在称为骨形态发生蛋白及其抑制剂的因子上，这些因子在调节心脏和血管方面很重要。了解这些因素如何起作用可能会导致新的预防和治疗策略。

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. PUBLIC HEALTH RELEVANCE: Our studies are relevant to the treatment of disease of the heart and vessels such as hardening of the arteries, which is common in patients with diabetes, and hereditary hemorrhagic telangiectasia, a hereditary disease. Our studies focus on factors called bone morphogenetic proteins and their inhibitors, which are important in regulating the heart and vessels. Understanding how these factors work may lead to new strategies for prevention and treatment.