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（BMPs）正在成为脉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发挥重要作用。我们的数据表明，内皮细胞BMP4活性导致两种BMP抑制剂，基质Gla蛋白（MGP）和Crossveinless-2 （Cv2）的顺序诱导。MGP抑制BMP4，当缺乏时，允许内皮、血管钙化和avm中出现干细胞标记物。缺乏Cv2导致内皮细胞异常增厚，而不增加干细胞标记物。我们的数据表明了一个两步模型，其中MGP调节血管祖细胞的增殖和干细胞特性，Cv2调节承诺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调节血管祖细胞池的大小。因此，增强的BMP4活性或降低的MGP将允许多能祖细胞成骨，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。特异性目标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

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.